EA015821B1 - Tricyclic nitrogen containing compounds as antibacterial agents - Google Patents

Abstract

Tricyclic nitrogen containing compounds of Formula (I)in which Zand Zare independently selected from CH and N and their use as antibacterials.

Description

This invention relates to new compounds containing their compositions and their use as antibacterial agents, including use in the treatment of tuberculosis.

B νθ 02/08224, νθ 02/50061, νθ 02/56882, νθ 02/96907, νθ 2003087098, νθ 2003010138, νθ 2003064421, νθ 2003064431, νθ 2004002992, νθ 2004002490, νθ 2004014 361, 2004040240, , νθ 2004058144, νθ 2004087145, νθ 2006002047, νθ 2006014580, νθ 2006010040, νθ 2006017326, νθ 2006012396, νθ 2006017468, νθ 2006020561, νθ 2006081179, νθ 2006081264, θθ609 / 40474, νθ 02/07572, νθ 2004024712, νθ 2004024713, νθ 2004035569, νθ 2004087647, νθ 2004089947, νθ 2005016916, νθ 2005097781, νθ 2006010831, νθ 2006021448, νθ θθ6026060260260 νθ 06137485, νθ 06105289, νθ 06125974, νθ 06134378, νθ 07016610, νθ 07081597, νθ 07071936, νθ 07115947, νθ 07118130, νθ 07122258, νθ 08006648, θθ0νθ08 a, naphthyridine, morpholine, cyclohexane, piperidine and piperazine having antibacterial activity. Νθ 2004104000 discloses tricyclic fused cyclic compounds capable of selective action on cannabinoid receptors. In νθ 2003048081, νθ 2003048158 and I82003232804 disclosed glycine amides as inhibitors of factor Xa.

This invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or Ν-oxide thereof

A — νρ ^ζ —ik ⁵

in which Ζ ¹ and Ζ ^{2 are} independently selected from CH and Ν;

K ^1a and K ^{1b are} independently selected from hydrogen; halogen; cyano; (C1 _-6 ) alkyl; (C1 _-6 ) alkylthio; trifluoromethyl; trifluoromethoxy; carboxy; hydroxy, optionally substituted with ( _C1-6 ) alkyl or ( _C1-6 ) alkoxy substituted ( _C1-6 ) alkyl; (C1 _-6 ) alkoxy substituted (C1 _-6 ) alkyl; hydroxy (C1 _-6 ) alkyl; amino, optionally Ν-substituted by one or two (C1 _-6) alkyl, formyl, (C1-6) alkylcarbonyl or (C1-6) alkylsulfonyl groups; and aminocarbonyl, in which the amino group is optionally substituted with (C1 _-4 ) alkyl;

provided that K ^1a is H when обозначает ² is Ν and K ^1b is H when Ζ ¹ is Ν;

K ² denotes hydrogen or (C1 _-4) alkyl or together with R ⁶ forms Υ, as defined below;

A denotes a group (ί)

in which K ³ has the meanings defined for K ^1a and K ^1b , or denotes oxo, and n = 1 or 2; or A represents a group (ίί)

p □ / | o 7 E / 1 o 1 in which ν, ν and ν denote SK K or ν and ν denote SK K and ν denotes the relationship between ν ³ and Ν;

X is O, SK ⁴ K ⁸ or ΝΒ ⁶ ;

one K ⁴ has the meanings defined for K ^1a and K ^1b , and the rest and K ⁸ denote hydrogen or one K ⁴ and K ⁸ together denote oxo, and the rest denote hydrogen;

K ⁶ is hydrogen or (C1 _-6) alkyl or together with R ² forms Υ;

K ⁷ is hydrogen; halogen; hydroxy, optionally substituted with ( _C1-6 ) alkyl; or (C1 _-6 ) alkyl;

Υ is SK ⁴ K ⁸ CH ₂ ; CH ₂ SC ⁴ K ⁸ ; (C = O); SK ⁴ K ⁸ ; SK ⁴ K ⁸ (C = O) or (C = O) SK ⁴ K ⁸ or, when X is SK ⁴ K ⁸ , K ⁸ and K ⁷ together denote a bond;

and selected from CO and CH ₂ and

K ⁵ denotes, if necessary, a substituted bicyclic carbocyclic or heterocyclic ring system (B)

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containing up to four heteroatoms in each ring, in which at least one of the rings (a) and (b) is aromatic;

X ¹ is C or Ν when it is part of an aromatic ring, or CJ ¹⁴ when it is part of a non-aromatic ring;

X ² denotes Ν, ΝΚ ¹³ , O, 8 (O) _X , CO, or SY ¹⁴ when it is part of an aromatic or non-aromatic ring, or may also indicate SY ¹⁴ I ¹⁵ when it is part of a non-aromatic ring;

X ³ and X ⁵ independently represent N or C;

Υ ¹ denotes a linker group of 0-4 atoms, each atom of which is independently selected from Ν, NЯ ¹³ , О, 8 (О) _X , СО and СЯ ¹⁴ , when it is part of an aromatic or non-aromatic ring, or may additionally be СЯ ¹⁴ I am ¹⁵ when it is part of a non-aromatic ring;

Υ ² denotes a linker group of 2-6 atoms, each atom Υ ² independently selected from Ν, NЯ ¹³ , О, 8 (О) _X , СО, СЯ ¹⁴ , when it is part of an aromatic or non-aromatic ring, or may additionally be SE ¹⁴ I ¹⁵ when it is part of a non-aromatic ring;

each of I ¹⁴ and I ^{15 is} independently selected from H; (C _1-4 ) alkylthio; halogen; carboxy (C _1-4 ) alkyl; (C _1-4 ) alkyl; (C _1-4 ) alkoxycarbonyl; (C _1-4 ) alkylcarbonyl; (C _1-4 ) alkoxy (C _1-4 ) alkyl; hydroxy; hydroxy (C _1-4 ) alkyl; (C _1-4 ) alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl, optionally mono- or disubstituted (C1-4) alkyl; or

I ¹⁴ and I ¹⁵ can together mean oxo;

each I ¹³ independently represents H; trifluoromethyl; (C _1-4 ) alkyl, optionally substituted with hydroxy, (C _1-6 ) alkoxy, (C _1-6 ) alkylthio, halogen or trifluoromethyl; (C _2-4 ) alkenyl; (C1-4) alkoxycarbonyl; (C1-4) alkylcarbonyl; (C1-6) alkylsulfonyl; aminocarbonyl in which the amino group is optionally mono- or disubstituted with (C1-4) alkyl; and each x independently means 0, 1 or 2.

This invention also relates to a method for treating bacterial infections, including tuberculosis, in mammals, especially humans, comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or окс-oxide thereof.

The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or Ν-oxide thereof, in the manufacture of a medicament for use in the treatment of bacterial infections, including tuberculosis, in mammals.

The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or Ν-oxide thereof and a pharmaceutically acceptable carrier.

In one aspect, one of Ζ ¹ and Ζ ² is CH or Ν, and the other is CH.

In private aspects:

(ί) Ζ ¹ and Ζ ² , both, denote CH;

(ίί) Ζ ¹ is Ν, Ζ ² is CH;

ϊϊΐ) Ζ ¹ stands for CH, Ζ ² stands for Ν.

In a particular aspect, H ^1a and H ^1b independently represent hydrogen, (C _1-4 ) alkoxy, (C _1-4 ) alkylthio, (C1-4) alkyl, cyano, carboxy, hydroxymethyl or halogen; more specifically, hydrogen, methoxy, methyl, cyano or halogen.

In particular embodiments, H ^1a and H ^1b are hydrogen.

In a particular aspect, I ² is hydrogen.

Particular examples of I ³ include hydrogen; optionally substituted hydroxy; optionally substituted amino; halogen; (C1-4) alkyl; 1-hydroxy (C1-4) alkyl; optionally substituted aminocarbonyl. More specifically, I ³ is hydrogen; CONH2; 1-hydroxyalkyl, e.g. CH2OH; optionally substituted hydroxy, for example methoxy; optionally substituted amino; and halogen, in particular fluorine. Most preferably, I ³ is hydrogen, hydroxy or fluoro.

In a particular aspect, when A is (1a), n = 1. In another aspect, I ³ is position 3 or 4. In a more particular aspect, A is (1a), n = 1, and I ³ is in position 3, more specifically, in the cis position with respect to the ΝΒ ² group. In particular embodiments, A is a group (1a) in which n is 1 and H ³ is hydrogen or hydroxy. More specifically, if A is

3-hydroxypiperidin-4-yl, the configuration is (3H, 48) or (38,4H). Alternatively and more specifically, if A is piperidin-4-yl, the configuration is configuration (3H, 48).

In an alternative, more particular aspect, when A is (1a), n = 1, ³ is in position 4 and is methyl.

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In a particular aspect, when A is (ίί), X is SK ⁴ K ⁸ , K ⁸ is H and K ⁴ is H or OH and, more specifically, OH is in a trans position with respect to K ⁷ . In another aspect, XV ¹ is a bond. In another aspect, K ⁷ is H. In an additional aspect, V ¹ is a bond, V ² and V ³ are both CH ₂ and K ⁷ is H. If A is 4-hydroxypyrrolidin-3-ylmethyl, in a particular aspect, the configuration is a configuration (38.48). If A is pyrrolidin-3-methylmethyl, in a particular aspect, the configuration is configuration 38.

In a particular aspect, when A is (ίί), X is O, K ⁷ is H and V ¹ , V ² and V ³ are each CH ₂ .

In some embodiments, the implementation and denotes CH ₂ .

In some embodiments, K ⁵ is an aromatic heterocyclic ring (B) having 8-11 ring atoms, including 2-4 heteroatoms, of which at least one is N or ΝΒ ¹³ , in which, in particular embodiments, Υ ² contains 2-3 heteroatoms, one of which is 8 and 1-2 are Ν, and one N is bonded to X ³ .

In alternative embodiments, the heterocyclic ring (B) has an aromatic ring (a), optionally selected from substituted benzo, pyrido, pyridazino and pyrimidino, and ring (b) is non-aromatic, and Υ ² has 3-5 atoms, more specifically 4 atoms including at least one heteroatom where O, 8, CH2 or ΝΒ ¹³ is bonded to X ⁵ , wherein K ¹³ is different from hydrogen and either ΝΗίΌ is bonded through N to X ³ , or O, 8, CH2 or ΝΗ is bonded to X ³ . In a particular aspect, ring (a) contains aromatic nitrogen, more specifically, ring (a) is pyridine or pyrazine. Examples of rings (B) include, if necessary, substituted:

(a) and (b) are aromatic:

1H-pyrrolo [2,3-b] pyridin-2-yl, 1H-pyrrolo [3,2-b] pyridin-2-yl, 3H-imidazo [4,5-b] pyrid-2-yl, 3H- quinazolin-4-one-2-yl, benzimidazol-2-yl, benzo [1,2,3] thiadiazol-5-yl, benzo [1,2,5] oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo [b] thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo [1,2-a] pyridin-2-yl, imidazo [1, 2-a] pyrimidin-2-yl, indol-2-yl, indol-6-yl, isoquinolin-3-yl, [1,8] naphthyridin-3-yl, oxazolo [4,5-b] pyridin-2 -yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, naphthalene-2-yl, 1,3-dioxoisoindol-2-yl, 1H-benzotriazol-5-yl, 1H-indol-5 -yl, 3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thion-6-yl, 3H-be nzothiazol-2-one-5-yl, 3H-quinazolin-4-one-6-yl, pyrido [1,2-a] pyrimidin-4-one-3-yl (4-oxo-4H-pyrido [1, 2-a] pyrimidin-3-yl), benzo [1,2,3] thiadiazol-6-yl, benzo [1,2,5] thiadiazol-5-yl, benzo [1,4] oxazin-2-one -3-yl, benzothiazol-5-yl, benzothiazol-6-yl, cinnolin-3-yl, imidazo [1,2-b] pyridazin-2-yl, pyrazolo [1,5-a] pyrazin-2-yl , pyrazolo [1,5-a] pyridin-2-yl, pyrazolo [1,5-a] pyrimidin-6-yl, pyrazolo [5,1-s] [1,2,4] triazin-3-yl, pyrido [1,2-a] pyrimidin-4-one-2-yl (4-oxo-4H-pyrido [1,2-a] pyrimidin-2-yl), quinazolin-2-yl, quinoxaline-6-yl , thiazolo [3,2-a] pyrimidin-5-one-7-yl, thiazolo [5,4-b] pyridin-2-yl, thieno [3,2-b] pyridin-6-yl, thiazolo [5,4-b] pyridin-6-yl, thiazolo [4,5-b] pyridin-5-yl, [1,2,3] thiadiazolo [5,4-b] pyridin-6-yl, 2H- isoquinolin-1-one-3-yl (1-oxo-1,2-dihydroisoquinolin-3-yl), [1,2,3] thiadiazolo [5,4-b] pyridin-6-yl.

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-> indicates the point of attachment (a) is non-aromatic:

(28) -2,3-dihydro-1H-indol-2-yl, (28) -2,3-dihydrobenzo [1,4] dioxin-2-yl,

3- (I, 8) -3,4-dihydro-2H-benzo [1,4] thiazin-3-yl, 3- (I) -2,3-dihydro [1,4] dioxino [2,3- B] pyridin-3-yl,

3- (8) -2,3-dihydro [1,4] dioxino [2,3-b] pyridin-3-yl, 2,3-dihydrobenzo [1,4] dioxan-2-yl,

3-substituted-3H-quinazolin-4-one-2-yl

-> denotes the point of attachment (b) is non-aromatic:

1.1.3-trioxo-1,2,3,4-tetrahydro-1 ^6- benzo [1,4] thiazin-6-yl, benzo [1,3] dioxol-5-yl,

2.3-dihydrobenzo [1,4] dioxin-6-yl, 3-substituted-3H-benzooxazol-2-one-6-yl,

3-substituted-3H-benzooxazol-2-thion-6-yl, 3-substituted-3H-benzothiazol-2-one-6-yl, 4H-benzo [1,4] oxazin-3-one-6-yl ( 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl), 4H-benzo [1,4] thiazin-3-one-6-yl (3-oxo-3,4 -dihydro-2H-benzo [1,4] thiazin-6-yl), 4H-benzo [1,4] oxazin-3-one-7-yl, 4-oxo-2,3,4,5-tetrahydrobenzo [ B] [1,4] thiazepin-7-yl,

5-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-6-yl, 1H-pyrido [2,3-b] [1,4] thiazin-2-one-7-yl (2-oxo-2,3-dihydro-1H-pyrido [2,3-b] thiazin-7-yl),

2.3-dihydro-1H-pyrido [2,3-b] [1,4] thiazin-7-yl, 2-oxo-2,3-dihydro-1H-pyrido [3,4-b] thiazin-7-yl ,

2.3-dihydro [1,4] dioxino [2,3-b] pyridin-6-yl, 2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-yl,

2.3-dihydro [1,4] dioxino [2,3-b] pyridin-7-yl, 3,4-dihydro-2H-benzo [1,4] oxazin-6-yl,

3.4-dihydro-2H-benzo [1,4] thiazin-6-yl, 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl,

3.4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl,

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl, 3,4-dihydro-1H-quinolin-2-one-7-yl,

3.4-dihydro-1H-quinoxalin-2-one-7-yl, 6,7-dihydro-4H-pyrazolo [1,5-a] pyrimidin-5-on-2-yl,

5,6,7,8-tetrahydro [1,8] naphthyridin-2-yl (1,2,3,4-tetrahydro [1,8] naphthyridin-7-yl),

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2-oxo-3,4-dihydro -1H - [1,8] naphthyridin-6-yl,

6-oxo-6,7-dihydro-5H-pyridazino [3,4-b] [1,4] thiazin-3-yl (6-oxo-6,7-dihydro-5H-8-thia-1,2 5-triazanaphthalen-3-yl),

2-oxo-2,3-dihydro-1H-pyrido [3,4-b] [1,4] oxazin-7-yl, 2-oxo-2,3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazin-7-yl,

6.7-dihydro [1,4] dioxino [2,3-4] pyrimidin-2-yl, [1,3] oxathiolo [5,4-c] pyridin-6-yl,

3.4-dihydro-2H-pyrano [2,3-s] pyridin-6-yl, 2,3-dihydro [1,4] oxathiino [2,3-s] pyridin-7-yl,

6.7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-yl, 5,6,7,8-tetrahydroisoquinolin-3-yl,

6.7-dihydro-5H-cyclopenta [s] pyridin-3-yl, 1,3-dihydrofuro [3,4-s] pyridin-6-yl,

3.4-dihydro-2H- [1,4] oxathiepino [2,3-s] pyridin-8-yl, [1,3] oxathiolo [4,5-s] pyridin-6-yl,

6.7-dihydro [1,4] oxathiino [2,3-s] pyridazin-3-yl, 6,7-dihydro-5H-pyrano [2,3-s] pyridazin-3-yl,

5.6-dihydrofuro [2,3-c] pyridazin-3-yl, 2,3-dihydrofuro [2,3-c] pyridin-5-yl, 2-substituted with 1H-pyrimido [5,4-b] [1, 4] oxazin-7 (6H) -one, 2-substituted 5,6-dihydropyrido [2,3-ά] pyrimidin-7 (1H) -one,

7-substituted 2H-chromen-2-one, 7-substituted 2H-pyrano [2,3-b] pyridin-2-one, 2-substituted 6,7-dihydro-5H-pyrano [2,3-ά] pyrimidine ,

8-substituted 2H-pyrido [1,2-a] pyrimidin-2-one, 2,3-dihydro-1-benzofuran-5-yl, 1H-pyrimido [5,4-b] [1,4] thiazin- 7 (6H) -on-2-yl, 3,4-dihydro-2H-chromen-7-yl,

2.3-dihydro-1-benzofuran-6-yl, 3,4-dihydro-2H-chromen-6-yl,

3.4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6- silt

6.7-dihydro-5H-thieno [3,2-b] pyran-2-yl, 2,3,4,5-tetrahydro-1,5-benzothiazepin-7-yl.

where K is an additional substituent; -> indicates the point of attachment.

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In some embodiments, K ¹³ is H if it is in ring (a), or, in addition, (C1_4) alkyl, such as methyl or isopropyl, when it is in ring (b). More specifically, in the ring (b), K ¹³ is H when ΝΚ ¹³ is bonded to X ³ , and (C1-4) is alkyl when ΝΚ ¹³ is bonded to X ⁵ .

In other embodiments, K ¹⁴ and K ^{15 are} independently selected from hydrogen, halogen, hydroxy, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, nitro, and cyano. More specifically, K ¹⁵ is hydrogen.

More specifically, each K ^{14 is} selected from hydrogen, chlorine, fluorine, hydroxy, methyl, methoxy, nitro and cyano. Even more specifically, K ^{14 is} selected from hydrogen, fluorine or nitro.

Most preferably, K ¹⁴ and K ¹⁵ are each N.

Specific K ⁵ groups include:

[1.2.3] thiadiazolo [5,4-b] pyridin-6-yl; 1H-pyrrolo [2,3-b] pyridin-2-yl;

2,3-dihydro [1,4] dioxino [2,3-b] pyridin-6-yl;

2,3-dihydro [1,4] dioxino [2,3-b] pyridin-7-yl;

2.3-dihydro [1,4] dioxino [2,3-c] pyridin-7-yl;

2.3-dihydrobenzo [1,4] dioxin-6-yl;

2-oxo-2,3-dihydro-1H-pyrido [2,3-b] [1,4] oxazin-7-yl;

2-oxo-2,3-dihydro-1H-pyrido [2,3-b] [1,4] thiazin-7-yl;

3.4-dihydro-2H-benzo [1,4] oxazin-6-yl;

3-methyl-2-oxo-2,3-dihydrobenzooxazol-6-yl; 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl;

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl;

3-oxo-3,4-dihydro-2H-benzo [1,4] thiazin-6-yl (4H-benzo [1,4] thiazin-3-one-6-yl);

4-oxo-4H-pyrido [1,2-a] pyrimidin-2-yl;

6-nitrobenzo [1,3] dioxol-5-yl;

7-fluoro-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl;

8-hydroxy-1-oxo-1,2-dihydroisoquinolin-3-yl;

8-hydroxyquinolin-2-yl;

benzo [1,2,3] thiadiazol-5-yl;

benzo [1,2,5] thiadiazol-5-yl;

benzothiazol-5-yl;

thiazolo [5,4-b] pyridin-6-yl;

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl;

7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl;

7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl;

7-fluoro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl;

2-oxo-2,3-dihydro-1H-pyrido [3,4-b] [1,4] thiazin-7-yl;

[1.3] oxathiolo [5,4-c] pyridin-6-yl;

3.4-dihydro -2H-pyrano [2,3-c] pyridin-6-yl;

5-carbonitro-2,3-dihydro-1,4-benzodioxin-7-yl;

2.3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-yl;

6.7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-yl;

5,6,7,8-tetrahydroisoquinolin-3-yl;

6.7-dihydro-5H-cyclopenta [s] pyridin-3-yl;

1.3-dihydrofuro [3,4-c] pyridin-6-yl;

6-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl;

3.4-dihydro-2H- [1,4] oxathiepino [2,3-c] pyridin-8-yl;

[1.3] oxathiolo [4,5-s] pyridin-6-yl;

2,3-dihydro-1-benzofuran-5-yl;

6.7-dihydro [1,4] oxathiino [2,3-c] pyridazin-3-yl;

6.7-dihydro-5H-pyrano [2,3-c] pyridazin-3-yl;

5.6-dihydro furo [2,3-c] pyridazin-3-yl;

2-substituted 1H-pyrimido [5,4-b] [1,4] oxazin-7 (6H) -one;

2-substituted 4-chloro-1H-pyrimido [5,4-b] [1,4] oxazin-7 (6H) -one;

2-substituted 5,6-dihydropyrido [2,3-th] pyrimidin-7 (1H) -one;

2-substituted 4-chloro-5,6-dihydropyrido [2,3-ά] pyrimidin-7 (1 H) -one;

2-substituted 4-methyl-5,6-dihydropyrido [2,3-ά] pyrimidin-7 (1 H) -one;

2-substituted 4-methyloxy-5,6-dihydropyrido [2,3-0] pyrimidin-7 (1H) -one;

7-substituted 2H-chromen-2-one;

7-substituted 2H-pyrano [2,3-b] pyridin-2-one;

4-chloro-6,7-dihydro-5H-pyrano [2,3-ά] pyrimidin-2-yl;

8-substituted 2H-pyrido [1,2-a] pyrimidin-2-one;

6.7-dihydro-5H-pyrano [2,3-ά] pyrimidin-2-yl;

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5-chloro-1-benzothiophen-2-yl;

6-chloro-1-benzothiophen-2-yl;

1-benzothiophen-5-yl; 1-methyl-1H-1,2,3-benzotriazol-6-yl;

imidazo [2,1-b] [1,3] thiazol-6-yl;

4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl; 1-methyl-1H-indol-2-yl;

1H-pyrimido [5,4-b] [1,4] thiazin-7 (6H) -on-2-yl; [1,2,5] thiadiazolo [3,4-b] pyridin-6-yl;

4-fluoro-1H-benzimidazol-2-yl;

3,4-dihydro-2H-chromen-7-yl;

2.3-dihydro-1-benzofuran-6-yl;

3.4-dihydro-2H-chromen-6-yl;

6-chloro-2,3-dihydro-1,4-benzodioxin-7-yl;

7-chloro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl;

7-chloro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl;

3.4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl;

5-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl;

5-fluoro-2,3-dihydro -1,4-benzodioxin-6-yl;

8-fluoro-2H-1,4-benzoxazin-3 (4H) -on-6-yl; 8-fluoro-3,4-dihydro-2H-1,4-benzoxazin-6-yl;

7.8-difluoro-3,4-dihydro-2H-1,4-benzoxazin-6-yl;

6,7-dihydro-5H-thieno [3,2-b] pyran-2-yl; 5-methyl-2,3-dihydro-1,4-benzodioxin-7-yl;

4-oxo-2,3,4,5-tetrahydro -1,5-benzothiazepin-7-yl;

3.4-dihydro -2H -1,4-benzothiazin-6-yl;

2,3,4,5-tetrahydro -1,5-benzothiazepin-7-yl;

7-fluoro-3,4-dihydro-2H-1,4-benzoxazin-6-yl.

- 7 015821

Η

about

-> indicates the point of attachment; special

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl;

3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl;

2.3-dihydro [1,4] dioxino [2,3-c] pyridin-7-yl;

[1,3] oxathiolo [5,4-c] pyridin-6-yl;

6-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl;

2.3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-yl;

3.4-dihydro-2H-pyrano [2,3-c] pyridin-6-yl;

5-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl;

5-carbonitro-2,3-dihydro-1,4-benzodioxin-7-yl;

2,3-dihydrobenzo [1,4] dioxin-6-yl

-> indicates the point of attachment.

In the framework of the invention, the term alkyl includes straight and branched chain groups, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. The term alkenyl should be interpreted accordingly.

- 8 015821

Halogen includes fluorine, chlorine, bromine and iodine.

Halogenated contains 1-3 halogen atoms.

Compounds within the scope of the invention contain a heterocyclyl group and may occur in two or more tautomeric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included in the scope of the invention.

Some of the compounds of the invention may be crystallized or recrystallized from solvents, such as aqueous and organic solvents. In such cases, solvates can be formed. This invention includes stoichiometric solvates, including hydrates, as well as compounds containing varying amounts of water that can be prepared by methods such as lyophilization.

In addition, it should be understood that phrases such as a compound of formula (I) or a pharmaceutically acceptable salt or Ν-oxide thereof encompass a compound of formula (I), a Ν-oxide of formula (I), a pharmaceutically acceptable salt of a compound of formula (I ), a solvate of formula (I) or any pharmaceutically acceptable combination thereof. Thus, by way of non-limiting example used here for illustrative purposes, a compound of formula (I) or a pharmaceutically acceptable salt thereof may include a pharmaceutically acceptable salt of a compound of formula (I), which is furthermore in the form of a solvate.

Since the compounds of formula (I) are intended for use in pharmaceutical compositions, it is readily understood that in particular embodiments they are used in substantially pure form, for example with a purity of at least 60%, more preferably with a purity of at least 75 % and especially at least 85%, especially with a purity of at least 98% (% are by weight). The crude preparations of the compounds can be used to obtain the purer forms used in pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more preferably at least 5% and more specifically from 10% of the compound of formula (I) or a pharmaceutically acceptable salt and / or Ν-oxide thereof.

Specific compounds of the invention include those indicated in the examples and their pharmaceutically acceptable Ν-oxides, salts and solvates.

Pharmaceutically acceptable salts of the above compounds of formula (I) include acid addition salts or quaternary ammonium salts, for example salts thereof with inorganic acids, for example hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids, or with organic acids, for example acetic fumaric, succinic, maleic, citric, benzoic, p-toluenesulfonic, methanesulfonic, naphthalenesulfonic or tartaric acid. The compounds of formula (I) can also be obtained in the form of Ν-oxide. The invention extends to all such derivatives.

Some of the compounds of formula (I) may exist in the form of optical isomers, for example diastereoisomers and mixtures of isomers in all respects, for example racemic mixtures. The invention includes all such forms, in particular pure isomeric forms. For example, the invention includes enantiomers and diastereoisomers at the point of attachment of ΝΡ ² and K ³ . The various isomeric forms can be separated from one another by conventional methods or any given isomer can be obtained by conventional synthesis methods or by stereospecific or asymmetric synthesis. Some compounds of formula (I) may also exist in polymorphic forms, and the invention includes such polymorphic forms.

In a further aspect, the invention relates to a method for producing compounds of formula (I), where Ζ ² is nitrogen, and their pharmaceutically acceptable salts and / or Ν-oxides, comprising administering a compound of formula (PL)

(PA) in which L is a leaving group or —L (O ′) (O ² ), where O ′ and O ² are both attached to the same carbon atom on A, O ¹ is H, O ² is ^ K ²⁰ ) K ² ′ or O ¹ and O ² together form ethylenedioxy or oxo, K ²⁰ represents IR ⁵ or a group capable of converting to it, and K ² represents K ² or a group capable of converting to it, A, K ^1b , K ^2, and K ⁵ are as defined in formula (I), to react with (ί) ethyl bromoacetate followed by cyclisation and oxidation or (ίί) etiloksoatsetatom followed by cyclization to afford compound Formula (IIIA)

- 9 015821

and then, if necessary or as necessary, the conversion of L to -Ά-ΝΚ ² -ϋΚ ⁵ , the mutual conversion of any variable groups and / or the formation of a pharmaceutically acceptable salt and / or Ν-oxide.

A variant of reaction (1) is selective alkylation with ethyl bromoacetate under basic conditions (such as potassium carbonate) (see Υθ51ιίζ; · ι \ ν; · ι. N. c1 a1., Hc1cgosus1c5 (2004), 63 (8), 1757-1763 as an example of this selectivity in the alkylation of 2,3-diaminopyridines), thermal cyclization under strict basic conditions (such as potassium tert-butoxide) and then oxidation with manganese dioxide under ordinary conditions (see, for example, 8sh11y, M.V .; Magse , 1.M. Ayuapsey Ogdashs Syetsch1gu, ^ 11eu-1n1eg8S1epse, 2001).

Reaction option (ίί) can be carried out in toluene and cyclization can be carried out under strong basic conditions (such as potassium tert-butoxide).

B can be a hydroxyl group which can be oxidized to the aldehyde by conventional means, such as 1,1,1-tris- (acetyloxy) -1,1-dihydro-1,2-benzodiodoxol-3- (1H) -one for reducing alkylation with NL -> I ²⁰ ) I ² 'under ordinary conditions (see, for example, 8shPy, M.V .; Magsy, 1.M. Ayuapsey Ogdashs Syetsch1gu, ^ PeuPshegasepse, 2001).

Alternatively, b may be bromine, which may be alkylated with HL -> ²⁰ ) ² under normal conditions.

If O ¹ and O ² together form ethylenedioxy, the ketal can be converted to ketone (O ¹ and O ² together form oxo) by conventional acid hydrolysis, for example, with an aqueous solution of HCl or trifluoroacetic acid and conversion to ΝΚ, ΉΚ. ^{5 by} conventional reductive alkylation with an amine Ν№ ² Κ ²⁰ (see, for example, Nyetap, A., e! A1., Te1gaEyegop, 60 (2004), 1731-1748) and subsequent conversion to the desired substituted amine or directly with непосредственно ^ ϋΚ ⁵ , such as sodium triacetoxyborohydride in a dichloromethane / methanol mixture.

Preferably, one of H ²⁰ and H ² is a Ν-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl. It can be removed in several ways that are known to the person skilled in the art (for example, see Prococilliophthalmus ogdap / c8p1e8e8, T. \. Szheepe apy P.M. \ u18, PeuPshegasepse, 1999), for example, by conventional acid hydrolysis, for example, with trifluoroacetic or hydrochloric acid. The invention also relates to compounds of formula (ΙΙΙΑ), in which b is —A — Ν (Z ²⁰ ) Z ² ′ and Z ²⁰ is hydrogen.

The free amine of formula (ΙΙΙΑ), in which I ²⁰ denotes hydrogen, can be converted to \ 1EYA by conventional means, such as the formation of an amide with an acyl derivative I ⁵ СО \, for compounds where it means CO, or, if it means CH ₂ by alkylation with an alkyl halide I ⁵ CH2-halide in the presence of a base, acylation / reduction with an acyl derivative I ⁵ CO 1 or reductive alkylation with an aldehyde I ⁵ CHO under ordinary conditions (see, for example, 8tPE, M.V .; Magc, EM Ayuapsey Ogdashs Syetsch1gu, ^ PeuPshegaaepse, 2001). Suitable reagents containing the necessary groups of H ⁵ are known compounds or can be obtained analogously to known compounds, see, for example, \ O 02/08224, \ O 02/50061, \ O 02/56882, \\ 'O 02 / 96907, \\ 'O 2003087098, \\' O 2003010138, \\ 'O 2003064421, \\' O 2003064431, \\ 'O 2004002992, \\' O 2004002490, \ O 2004014361, \ O 2004041210, \ O 2004096982, \ O 2002050036, \ O 2004058144, \ O 2004087145, \ O 06002047, \ O 06014580, \ O 06010040, \ O 06017326, \ O 06012396, \ O 06017468, \ O 06020561, \ O 2004/035569, \ O 2004 / 089947, \ O 2003082835, \ O 06002047, \ O 06014580, \ O 06010040, \ O 06017326, \ O 06012396, \ O 06017468, \ O 06020561, \ O 06132739, \ O 06134378, \ O 06137485, \ O 06081179, \ O 06081264, \ O 06081289, \ O 06081178, \ O 06081182, \ O 07016610, \ O 07081597, \ O 07071936, \ O 07115947, \ O 07118130 , \ O 07122258, \ O 08006648, \ O 08003690, \ O 08009700, \ O 2007067511 and EP 0559285.

If R ⁵ contains a ΝΉ group, it can be protected by a suitable группой group protecting group, such as tert-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl, by combining the R ⁵ derivative with a free amine of formula (ΙΙΒ). The protecting group may be removed by conventional methods, such as trifluoroacetic acid treatment.

- 10 015821

In another aspect, the invention relates to a method for producing compounds of formula (I), where Ζ ¹ is nitrogen, and their pharmaceutically acceptable salts and / or Ν-oxides, comprising administering a compound of formula (ΙΙΒ)

in which L is a leaving group or -L (O ') (O ^:) . where O ¹ and O ^{2 are} attached to one and the same 1 EP '1 э the same carbon atom on A. 0 means H. O means Ν (Κ.) I or O and O together form ethylenedioxy or oxo. I ²⁰ means IY ⁵ or a group. able to turn into her. and I ² represents I ² or a group. able to turn into her. A. I am ^1a . I am ² . and and I ⁵ matter. defined in formula (I). reacting with (1) ethyl bromoacetate, followed by cyclization and oxidation, or with (ίί) ethyl oxoacetate, followed by cyclization. getting the compound of the formula (ΙΙΙΒ)

and after that, if necessary or as necessary, the transformation of b into -Α-NЯ ² -υЯ ⁵ . the mutual conversion of any variable groups and / or the formation of a pharmaceutically acceptable salt and / or Ν-oxide.

The reaction and subsequent transformations are carried out. as in the case of the preparation of compounds of formula (ΙΙΙΑ).

The invention also relates to compounds of formula (ΙΙΙΒ). in which b is -Α-Ν (Ρ ²⁰ ) Ρ ² and H ²⁰ is hydrogen.

Compounds of formula (ΙΙΒ) (Ε = -Α (Ο ¹ ) (Ο ² )) can be prepared according to Scheme 1.

Chloropyridine (2) can be reacted with allylamine to give (3). which can then be cyclized with the bromine-forming pyridone (4) after hydrolytic treatment (see 8ο1ιιηίά. 8. e1 a1 .. ZuySheyk. 2005 (18). 3107). An offset with Η-Αίφ'Χφ ² ) gives (5). and hydrogenation (5) using Ρά / C can give amine (6).

Compounds of formula (ΙΙΙΑ) can be prepared according to Scheme 2 using compounds of formula (ΙΥΑ)

The starting material can be obtained by the reaction of compound (3) from Scheme 1 with sodium methylate and then reduction with tin chloride (ΙΙ) or sodium dithionite. Cyclization (ΙΥΑ) with propiolate

- 11 015821 with esters yields (19) (Scheme 2) (see Ka1uapat, N. e! A1., Ιηάίαη 1оit1 оГ СёТЫгу, 8ес! -420). Standard protection, obtaining (20) and then cyclizing with bromine (see 8cbb14, 8. e! A1., 8up! Be515, 2005 (18), 3107) can then lead to an analog of bromomethyl (21), which can be reacted removal of the protective group from TPA to give (22) and oxidized with hydrogen peroxide or manganese dioxide (II) to give (23) (see 8aka! a, C., He! egosus1e8 (1985), 23 (1), 143-51 )

Scheme 2

Compounds of formula (I) in which Ζ ¹ and Ζ ² are both CH, can be prepared according to Scheme 3.

Scheme 3

(7) (ED

B denotes -A (C ') (C ² ).

(a) n-Butyllithium, dibromethane; (B) tris (dibenzylideneacetone) dipalladium (0), Ν, Ν-dicyclohexylmethylamine, bis- (tri-tert-butylphosphine) palladium (0), butyl acrylate; (c) hydrogen, palladium / charcoal, followed by treatment with acid (HC1); (ά) see text; (e) amine H-AYU'XC ² ), heating; (I) methanesulfonic anhydride, triethylamine, then ΚΙ; (e) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; (B) ί) ΌΜΓ, heating, ίί) methanesulfonyl chloride, triethylamine, ίίί) amine Н-АУ'ХС ² ), heating.

Metallization of (1) (commercially available) with n-butyl lithium followed by bromination with dibromethane gives the bromopyridine derivative (2) (see ΖΗκΗΗπ, P. e! A1., 8n1e11 (2006), (3), 379-382 as an example of this type chemistry of metallization).

Nesk reaction (2) using a palladium-based catalyst (see 8bogepto, Ν., E! A1., Ogdashs & Vyusho1si1b, SeshCBu (2005), 3 (11), 2140-2144 as an example of this type of catalysis in the Nesk reaction) gives acrylate (3). Hydrogenation of the double bond (3) followed by acid treatment to remove the pivalate residue and the effect of lactamation leads to bicyclic lactam (4). Conversion to epoxide (5) can be accomplished in a variety of ways — reaction with epichlorohydrin under basic conditions gives racemic epoxide.

- 12 015821

Reaction with (commercially available) K- or 8-glycidylnosylate ((2K) - or (28) -2-oxiranylmethyl-3-nitrobenzenesulfonate) or (2K) - or (28) -2-oxiranylmethyl-4-methylbenzenesulfonate with a base, for example a hydride sodium or potassium tert-butoxide, gives the corresponding chiral epoxides. Alternatively, allylation with allyl bromide under basic conditions gives the corresponding Ν-allyl, which can be epoxidized under standard achiral or chiral conditions, gives the corresponding achiral or chiral epoxides. Epoxide (s) (5) can be disclosed with amine Η-ΛίΟ'χρ ² ). such as 1,1-dimethylethyl-4-piperidinyl carbamate, by heating at ΌΜΕ to give (6), which can then be cyclized with methanesulfonic anhydride to give (7). Alternatively, epoxide (5) can be opened and cyclized directly by heating to give (7) (b = OH). The oxidation to (8) can be carried out by oxidation with 2,3dichloro-5,6-dicyano-1,4-benzoquinone (IIP). Subsequent conversion to compounds of formula (I) may be performed as generally described herein. In particular, the conversion of b to A (0 ') (0 ² ) can be carried out on (7) or (8). As a variant of Scheme 3, epoxide (5) can be obtained from (2) by first introducing a suitable precursor group of the epoxy group (—CH ₂ —CHOH — CH ₂ OH protected as a cyclic ether), followed by steps (b) and (c) .

The invention also relates to compounds of formula (8) from Scheme 3, wherein b is —A— → K ²⁰ ) K ² ′ and K ²⁰ is hydrogen.

Compounds of formula (I) wherein Ζ ² is Ν can alternatively be prepared according to Scheme 4.

Scheme 4

(a) 2-amino-1,3-propanediol; (B) dimethoxypropane, p-toluenesulfonic acid; (c) hydrogen, palladium / coal; (ά) ethyl bromoacetate, potassium carbonate; (e) sodium hydride; (ί) benzyl chloroformate; (e) an aqueous acid solution; (11) methanesulfonic acid anhydride; (ί) hydrogen, palladium / coal; ()) MnO ₂ .

Reaction of nitropyridine (1) with 2-amino-1,3-propanediol gives diol (2), which is protected as acetal (3). The reduction of the nitro group gives amine (4), which is alkylated to give an ester (5). The cyclization can be carried out using sodium hydride to obtain (6). It is protected by a carboxybenzyl (CB /) group (7), then cleaved to give a diol (8). Cyclization with Anhydri

- 13 015821 the methanesulfonic acid house gives the mesylate (9), then the hydrogenolysis of the CBx group (10) and subsequent oxidation with manganese (II) dioxide give the mesylate of the key intermediate dion (11). The order of the stages can be changed so as to go through stage (7a). Mesylate (11) can be converted to a compound of formula (I) as generally described herein.

Chiral compounds of formula (I) in which Ζ ² is Ν can alternatively be prepared according to Scheme 4a.

Bp is benzyl;

(a) CJS, reflux; (B) TB8-C1; (c) zinc, acetic acid; (ά) ethyl bromoacetate, potassium carbonate; (e) ΝαΗ; (ί) hydrogen, palladium / coal; (e) MnO ₂ ; (i) methanesulfonic acid anhydride (ί) TEL, (]) methanesulfonic acid anhydride.

The reaction of nitropyridine (1) with a chiral amine (2) gives an intermediate compound (3). Protection of (3) with tert-butyldimethylsilyl chloride affords (4). The reduction of the nitro group gives amine (5), which is alkylated to give an ester (6). The cyclization (6) can be carried out using sodium hydride, and then treatment with hydrogen using a catalyst based on palladium on carbon gives an intermediate compound (7). Oxidation with manganese (II) dioxide and treatment with methanesulfonic anhydride give (8). This intermediate may be subjected to a deprotection reaction using TEM to give (9) and reacted with methanesulfonic anhydride to give (10). The resulting mesylate (10) can then be converted to a compound of formula (I) as generally described herein.

Compounds of formula (I) in which Ζ ¹ is Ν can alternatively be prepared according to Scheme 5.

- 14 015821

Scheme 5

(11) (12)

B denotes -A (0 ') (0 ² ) (a) ΝΗ, / MeOH; (B) hydrogen, palladium / coal; (c)) ethyl bromoacetate, potassium carbonate; (ά) potassium tert-butoxide; (e) CBxC1; (ί) ΝαΗ; (8) -glycidyl nosylate; (e) ΌΜΕ, heating; (I) methanesulfonyl chloride (1) amine H-A (O ') (O ^:) . heating; (|) hydrogen, palladium / coal, then ΜηΟ ₂ .

The reaction of nitropyridine (1) with ammonia gives nitropyridine (2), which is reduced to bisaniline (3). Alkylation with ethyl bromoacetate followed by cyclization using potassium tert-butoxide gives (5). It is protected by a carboxybenzyl group to give (6), which can then be reacted with (commercially available) 8-glycidylnosylate ((28) -2-oxiranylmethyl-3nitrobenzenesulfonate) to give (7). Cyclization under heating gives (8). Mesylation, displacement with a suitable amine, hydrogenolysis of the CB / group (10) and subsequent oxidation with manganese (II) dioxide gives (13). Alternatively, hydrogenolysis of the CB / group (10) and subsequent oxidation with manganese (II) dioxide followed by mesylation and displacement with a suitable amine also gives (13). It can be converted into a compound of formula (I) as generally described herein.

The compounds of formula (I), in which Ζ ¹ and оба ² , both denoted by Ν, can be obtained in accordance with scheme 6.

Scheme 6

O) (a) chloroacetyl chloride; (B) ammonia; (c) Boc-glycine; (ά) HC1.

Compound (1) (Vyudaghs & άβάκίηα й 18 18 18 18 ей ей ег ег к к (((2005), 15 (24), 5446-5449) is converted to (2) by acylation using chloroacetyl chloride, followed by treatment with ammonia, to give (4). Alternatively, (1) can be converted to (3) by coupling with Boc-glycine followed by deprotection using an acid to give (4). Compound (4) can then be converted to a compound of formula (I) by analogy with the conversion of compound (5) from scheme 5.

Mutual conversions of K ^1a , K ^1b , K ² , A and K ^{5 are} carried out by conventional methods. In compounds that optionally contain a protected hydroxyl group, suitable conventional hydroxy protecting groups that can be removed without breaking the remainder of the molecule include acyl and alkylsilyl; Ν-protecting groups are removed by conventional means.

- 15 015821

The mutual transformation of the groups K ^1a and K ^1b can be performed by conventional methods on the compounds of formula (I). For example, K ^1a and K ^1b , which are methoxy, can be converted to K ^1a and K ^1b , which are hydroxy, treated with lithium and diphenylphosphine (the general method described by Mapy s1 a1., 1. Integ. Siet. 8os., 1973 7829) or HBr. Alkylation of the hydroxyl group with a suitable alkyl derivative bearing a leaving group, such as a halide, gives alkoxy substituted with K ^1a and K ^1b . K ^1a or K ^1b , which is a halogen such as bromine, can be converted to cyano by treatment with copper (I) cyanide in Ν, Ν-dimethylformamide. K ^1a or K ^1b , which is carboxy, can be obtained by conventional hydrolysis of K ^1a or K ^1b , which is cyano, and carboxy can be converted to hydroxymethyl by conventional reduction.

Compounds of the formula HA- ^ K ²⁰ ) K ² are known compounds or can be prepared analogously to known compounds, see, for example, VΟ 2004/035569, VΟ 2004/089947, VΟ 02/08224, VΟ 02/50061, VΟ 02/56882 , VΟ 02/96907, VΟ 2003087098, VΟ 2003010138, VΟ 2003064421, VΟ 2003064431, VΟ 2004002992, VΟ 2004002490, VΟ 2004014361, VΟ 2004041210, VΟ 2004096982, VΟ 2002050036, VΟ 2004058144, VΟ 2002020202308, 02300, 208 VΟ 06014580, VΟ 06134378, VΟ 06137485, VΟ 07016610, VΟ 07081597, VΟ 07071936, VΟ 07115947, VΟ 07118130, VΟ 07122258, VΟ 08006648, VΟ 08003690 and VΟ 08009700.

Further details of the preparation of compounds of formula (I) can be found in the examples.

The antibacterial compounds according to the invention can be formulated for administration in any convenient way for use in humans or in veterinary medicine, by analogy with other antibacterial / anti-tuberculosis compounds.

The pharmaceutical compositions of the invention can be formulated for administration by any route and include compositions in a form adapted for oral, topical or parenteral use and can be used to treat bacterial infections, including tuberculosis, in mammals, including humans.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, creams or liquid preparations, such as oral or parenteral sterile solutions or suspensions.

Topical formulations according to the present invention may be presented, for example, ointments, creams or lotions, eye ointments and eye or ear drops, soaked in bandages and sprays, and may contain suitable conventional additives, such as preservatives, solvents to facilitate the penetration of the drug and emollients into ointments and creams.

The compositions may also contain conventional compatible carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present in an amount of from about 1 to about 98% of the composition. More often they make up to about 80% of the composition.

Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients, such as binders, for example syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silicon dioxide; disintegrants, for example potato starch; or acceptable wetting agents, such as sodium lauryl sulfate. Tablets may be coated according to methods known in ordinary pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxyl methyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, for example lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerin, propylene glycol or ethanol; preservatives, for example methyl or propyl hydroxybenzoate, or sorbic acid, and, if desired, conventional flavors or colorants.

Suppositories may contain conventional suppository bases, for example cocoa butter or other glyceride.

For parenteral administration, liquid unit dosage forms are prepared using a compound and a sterile vehicle, preferably water. The compound, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved in water for injection and sterilized by filtration, followed by filling into a suitable vial or ampoule and sealing.

Preferably, agents such as local anesthetic, preservative and buffering agents can be dissolved in the carrier. To enhance stability, the composition may be frozen after filling into a vial and water may be removed in vacuo. The dry lyophilized powder is then sealed in a vial and an accompanying vial of water for injection can be applied to

- 16 015821 recovery fluid before use. Parenteral suspensions are prepared essentially in the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be carried out by filtration. The compound may be sterilized by the action of ethylene oxide before being suspended in a sterile vehicle. Preferably, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1 wt.%, Preferably 10-60 wt.% Of the active substance, depending on the method of administration. If the compositions include single doses, each dose preferably contains 50-1000 mg of the active ingredient. The dose when used for the treatment of an adult is preferably from 100 to 3000 mg per day, for example 1500 mg per day, depending on the route and frequency of administration. Such a dosage corresponds to from about 1.5 to about 50 mg / kg per day. Preferably, the dose is from 5 to 30 mg / kg per day.

The compound of formula (I) may be the only therapeutic agent in the compositions of the invention or in combination with other antibacterial agents, including anti-tuberculosis compounds. If the other antibacterial agent is β-lactam, then a β-lactamase inhibitor may also be used.

The compounds of formula (I) can be used in the treatment of bacterial infections caused by a variety of organisms, including both gram-negative and gram-positive organisms, such as upper and / or lower respiratory tract infections, skin and soft tissue infections and / or urinary tract infections. The compounds of formula (I) can also be used in the treatment of tuberculosis caused by Muscobacterium tuberculosis. Some compounds of formula (I) may be active against more than one organism. This can be determined by the methods described here.

The following examples illustrate the preparation of certain compounds of formula (I) and the activity of certain compounds of formula (I) against various bacterial organisms, including Muscobacillonummulci818.

Examples and experimental examples

Common abbreviations in the examples:

M8 is the mass spectrum;

E8 - electrospray mass spectroscopy;

LSMZ / LS-MZ - liquid chromatography with mass spectroscopy;

HPLC - high performance liquid chromatography;

g! - ambient temperature;

Κί - retention factor.

Some reagents are also indicated in abbreviations. TEA refers to trifluoroacetic acid, TUE refers to tetrahydrofuran, Ρά / C refers to a palladium-carbon catalyst, ESM refers to dichloromethane, MeOH refers to methanol, OME refers to dimethylformamide, ЕУАс refers to ethyl acetate, LLC refers to 2,3- dichloro-5,6-dicyano-1,4-benzoquinone, No. 1BH (OAc) ₃ , refers to sodium triacetoxyborohydride, Pb ₂ (ba) ₃ refers to tris- (dibenzylideneacetone) dipalladium (0).

Proton nuclear magnetic resonance spectra ( ¹ H NMR) were recorded at 400 or 250 MHz, chemical shifts are presented in parts per million (ppm) from the internal tetramethylsilane standard (TM8). The abbreviations for these NMR are as follows: k = singlet, b = doublet,! = Triplet, c = quartet, t = multiplet, bb = doublet of doublets, Y1 = doublet of triplets,! B = triplet of doublets, seem. = Apparent, wide. = broadened. ί indicates the NMR coupling constant measured in hertz. SESE stands for deuteriochloroform, CO ₃ OO stands for tetradeuteriomethanol. Mass spectra were obtained using electrospray ionization techniques (E8). All temperatures are in degrees Celsius.

MR carbonate refers to the macroporous triethylammonium methyl polystyrene carbonate (Agdopai! Tes11po1od1e5). Amberum ® ®A21 is a weakly basic macroporous resin with a functional alkylamino group, a registered trademark of the manufacturer Koit & Naak Co.

AO t1x a1rya was obtained by mixing potassium osmate (K ₂ OkO ₄ -2H ₂ O) (0.52 g), (3a, 9K, 3'a, 4'b, 9'K) -9.9 '[1, 4-phthalazinediyl-bis- (hydroxy)] - bis- [6 '- (methyloxy) -10,11-dihydrocinone] [(OHP) ₂ PHAI] (5.52 g), then adding potassium ferricyanide [K ₃ Her ( С№) ₆ ] (700 g) and potassium carbonate powder (294 g). This mixture is stirred in a stirrer for 30 minutes. This provides approximately 1 kg AO t1x a1rya, which is commercially available from A1ypsy. See K. Waggu 8yagr1e§5 e! A1., ί. Ogd. Siet., 1992, 57 (10), 2771. AO t1x L! A is the corresponding mixture obtained from (98.9'8) -9.9 '- [1,4phthalazinediyl bis- (hydroxy)] - bis - [6 '- (methyloxy) -10,11-dihydrocinchon] [(OHPO) ₂ PHAI]. If AO t1x a1pya / le! A is indicated, it is a 1: 1 mixture of alpha and beta.

Ce1e® is a filter aid made up of acid-washed diatomaceous earth and is a trademark of the manufacturer Mapushe Co., Denver, Colorado.

The 8CX cartridge is an ion exchange column containing a strong cation exchange resin (benzenesulfonic acid), supplied by Uapai, USA.

- 17 015821

Syga1rak ΙΑ and Syga1rak Α8-Η are polysaccharide-based chiral HPLC columns (Syga1 Tesypo1od1e8 Ιηο.). Column Syga1rak Α8-Η includes amylose-tris - [(8) -alphamethylbenzylcarbamate]. deposited on 5 μm silica gel. Column Silica рак includes silica gel for a preparative column (particle size 5 μm. 21 mm inner diameter x 250 mm length). immobilized amylose tris- (3.5-dimethylphenylcarbamate). The Syga1rak ΑΌ and ΑΌ-Η columns include silica gel for preparative columns (particle size 5 μm ΑΌ-Η and particle size 10 μm 21. 21 mm internal diameter x 250 mm length; particle size 20 μm ΑΌ. 101 mm internal diameter x 250 mm length ) coated with amylose-tris- (3.5-dimethylphenylcarbamate) The measured retention times depend on the exact conditions of the chromatographic procedures. If indicated below in the examples. they indicate the elution order. Column KgotakP 5 tyugop S-18 (21x250 mm) includes octadecylsilane. chemically bonded to porous silica gel with a pore size of 5 μm.

As will be clear to a specialist. indication of receipt. carried out in a similar or general manner. other acquisitions may cover variations in the usual parameters. such as time. temperature. processing conditions. minor changes in reagent quantities, etc.

Reactions. including metal hydrides. including lithium hydride. lithium aluminum hydride. diisobutylaluminum hydride. sodium hydride. sodium borohydride and sodium triacetoxyborohydride. carried out in an atmosphere of argon or other inert gas.

Example 1. 1 - ({4 - [(2.3-Dihydro [1.4] dioxino [2.3-s] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1.2-dihydro-3H.8H-2a.5.8 a-triazacenaphthylene-3.8-dione dihydrochloride

(a) 6-Chloro-3-nitro-2-propen-1-yl-2-pyridinamine.

He received a modification of the method 8s1pshCh 8 .. e! A1 .. 8Up! e518 (2005). (eighteen). 3107-3118. A solution of 2.6-dichloro-3-nitropyridine (8.0 g. 41.45 mmol) in anhydrous dichloromethane (180 ml) was cooled to -15 ° C in an argon atmosphere. Triethylamine (6.0 ml. 43 mmol) was added and then allylamine (3.23 ml. 43 mmol) was added in small portions over 3 hours. maintaining a temperature of -15 ° C. The reaction mixture was stirred overnight. during which it was heated to ambient temperature. The reaction mixture was washed with 0.2 M aqueous citric acid solution (100 ml). saturated aqueous solution (100 ml) of NaΗCΟz. passed through a hydrophobic frit and evaporated to a yellow oil. which was purified by silica gel chromatography eluting with 0 to 50% ethyl acetate in hexane. obtaining a yellow solid (7.49 g. 85%).

With ₈ H ₈ N ₃ O ₂ , 213 is required.

M8 (E8 +) t / ζ 214. 216 (MH ⁺ ).

(b) 3- (Bromomethyl) -8-nitro-2.3-dihydroimidazo [1.2-a] pyridin-5 (1H) -one.

He received a modification of the method 8s1pshCh 8 .. e! A1 .. 8Up! e518 (2005). (eighteen). 3107-3118. A solution of 6-chloro-3-nitro-No. 2-propen-1-yl-2-pyridinamine (20 g. 93.6 mmol) in chlorobenzene (500 ml) was treated with a solution. containing bromine (4.75 ml. 92.7 mmol) in chlorobenzene (100 ml). dropwise over 4.5 hours maintaining T <26 ° C upon cooling. If you want to. The thick suspension was stirred at ambient temperature for 18 hours and diluted with hexane (200 ml) and then the reaction mixture was poured into hexane (1000 ml). After 15 min, the orange precipitate was collected by filtration and washed with hexane (250 ml). yielding 26.6 g of an orange solid (3- (bromomethyl) -5-chloro-8-nitro-2.3-dihydroimidazo [1.2-a] pyridin-1-bromide). This intermediate compound was added. 45 minutes to a rapidly stirred mixture of a saturated aqueous solution (1000 ml) of NaΗCO ₃ and ethyl acetate (500 ml). The bright red mixture was stirred for 1 hour, diluted with ethyl acetate (200 ml) and the layers were separated. The aqueous layer was washed with ethyl acetate (200 ml) and the organic extracts were combined. dried (anhydrous sodium sulfate). filtered and evaporated. obtaining the product in the form of a brown solid (18.3 g. contains 40% 6-bromo-3- (bromomethyl) -8-nitro-2.3-dihydroimidazo [1.2a] pyridin-5 (1H) -one).

ί. ' ₈ Η ₈ ΒιΝ ₃ Ο ₃ , requires 273. M8 (E8 +) t / ζ 274. 276 (MH ⁺ ).

- 18 015821 (c) 1,1-Dimethylethyl {1 - [(8-nitro-5-oxo-1,2,3,5-tetrahydroimidazo [1,2-a] pyridin-3-yl) methyl] -4 piperidinyl } carbamate.

Suspension of a mixture of 3: 2 3- (bromomethyl) -8-nitro-2,3-dihydroimidazo [1,2-a] pyridin-5 (1H) -one and 6-bromo-3- (bromomethyl) -8-nitro 2,3-dihydroimidazo [1,2-a] pyridin-5 (1H) -one (18.2 g) was treated with 1,1-dimethylethyl-4-piperidinyl carbamate (26.6 g, 132.8 mmol) in acetonitrile ( 900 ml), then pyridine (10.7 ml, 132 mmol). The mixture was heated at 60 ° C. under argon for 17 hours and then heated at 70 ° C. for 2 hours, cooled and evaporated to about half the volume. A thick yellow precipitate was removed by filtration and washed well with diethyl ether. The filtrate was evaporated to dryness and the residue was partitioned between chloroform (500 ml) and water (200 ml). Insoluble material was removed by filtration and washed with chloroform (100 ml). The layers in the filtrate were separated and the aqueous layer was washed with chloroform (200 ml). The combined organic extracts were passed through a hydrophobic frit and evaporated to a dark yellow gum, which was chromatographed, eluting with 0 to 100% ethyl acetate in hexane, then 0 to 30% methanol in ethyl acetate, to give a yellow solid (10.98 g )

requires 393, M8 (E8 +) t / ζ 394 (MH ⁺ ).

(ά) 1,1-Dimethylethyl {1 - [(3,8-dioxo-1,2,5a, 8L-tetrahydro-3H, 8H-2a, 5,8a-triazacenaphthylene-1 yl) methyl] -4-piperidinyl }carbonate.

Suspension of 1,1-dimethylethyl {1 - [(8-nitro-5-oxo-1,2,3,5-tetrahydroimidazo [1,2-a] pyridin-3yl) methyl] -4-piperidinyl} carbamate (2, 0 g, 5.08 mmol) and anhydrous potassium carbonate (700 mg, 5.06 mmol) in absolute alcohol (150 ml) were hydrogenated at atmospheric pressure in the presence of 10% Ρά on C (1 g) for 4 hours. The reaction mixture filtered through KeBeZiig washed with ethanol (100 ml) and the dark violet mixture was immediately reacted by treatment with anhydrous potassium carbonate (1.4 g, 10 mmol) and ethyl bromoacetate (550 μl, 4.95 mmol), stirred at ambient temperature flowed e 20 hours and then heated at 60 ° C for 30 min. After 45 minutes, an additional amount of 0.25 ml of ethyl bromoacetate was added and heated at 60 ° C for 1.5 hours. 0.25 ml of ethyl bromoacetate was added and the reaction mixture was again heated at 60 ° C for 1 hour. The reaction mixture was filtered through KeBeZiig and evaporated to dryness. The mixture was azeotroped with chloroform and then chromatographed eluting with 0 to 100% ethyl acetate in hexane and then 0 to 20% methanol in ethyl acetate. A second elution using from 0 to 50% methanol in ethyl acetate gave a dark gum (37 mg, 1.6%).

With ₂₀ H ₂₇ N ₅ O ₂ requires 401, M8 (E8 +) t / ζ 402 (MH ⁺ ).

(f) 1 - [(4-amino-1-piperidinyl) methyl] -1,2,5a, 8b-tetrahydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8dione.

A solution of 1,1-dimethylethyl {1 - [(3,8-dioxo-1,2,5a, 8L-tetrahydro-3H, 8H-2a, 5,8a-triazacenaphthylene-1yl) methyl] -4-piperidinyl} carbamate ( 37 mg, 0.092 mmol) in anhydrous dichloromethane (2 ml) was treated with TEM (1 ml) and stirred at ambient temperature for 1 h, evaporated to dryness, mixed with anhydrous dichloromethane and evaporated to a dark gum. This resin was dissolved in 1: 1 dichloromethane: methanol (10 ml) and treated with an MP-carbonate resin (600 mg) and stirred for 1.5 hours. The reaction mixture was filtered, the resin was washed with 1: 1 dichloromethane: methanol (30 ml) ) and the filtrate was evaporated to dryness. Column purification 5 g of 8CX eluting with a gradient from methanol to 2n. methanol ammonia gave the product in the form of a resin. Further evaporation from diethyl ether gave the product as a brown solid (22.8 mg, 82%).

C ₁₅ H _{19 4} O ₂ requires 301, M8 (E8 +) t / ζ 302 (MH ⁺ ).

(1) Target compound.

Solution 1 - [(4-amino-1-piperidinyl) methyl] -1,2,5а, 8L-tetrahydro-3Н, 8Н-2а, 5,8а-triazacenaphthylene 3,8-dione (22.8 mg, 0.0757 mmol) in anhydrous dichloromethane (3 ml) and anhydrous methanol (0.6 ml) was treated with 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (12.5 mg, 0.076 mmol ) (for synthesis see UO 2004058144, example 2 (c) or UO 03/087098 example 19 (ά)), stirred under argon for 15 min and then treated with sodium triacetoxyborohydride (48 mg, 0.226 mmol) and stirred at ambient temperature for 17 hours. The reaction mixture was then treated with an additional A portion of 2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-carbaldehyde (2 mg) and sodium triacetoxyborohydride (10 mg), the mixture was stirred for 4 hours, treated with saturated aqueous NaHCO ₃ solution (1 ml) and stirred for 10 minutes The layers were separated and the aqueous layer was washed with a 9: 1 solution of dichloromethane: methanol (2x10 ml). The combined organic extracts were passed through a hydrophobic frit and evaporated to a brown gum, which was chromatographed eluting with 0 to 30% methanol in dichloromethane to give the free base of the title compound as a yellow gum (20.6 mg, 60%).

C ₂₃ H ₂₆ X ₆ O ₄ requires 450,

M8 (E8 +) t / ζ 451 (MH ⁺ ).

Ή NMR (250 MHz) (СОС1 ₃ ) δ 1.38-1.54 (2Н, m), 1.83-1.93 (2Н, m), 2.19-2.36 (2Н, m), 2.54-2.73 (3H, m), 2.93-2.98 (1H, m), 3.09-3.15 (1H, m), 3.85 (2H, s), 4, 26-4.61 (6H, m), 4.96-5.05 (1H, m), 6.33 (1H, ά), 6.82 (1H,

- 19 015821

s), 7.76 (1H, s), 7.87 (1H, s) and 8.10 (1H, s).

This free base of the target compound was dissolved in anhydrous dichloromethane (2 ml) and anhydrous methanol (0.5 ml) and treated with 1 M HC1 in diethyl ether (0.5 ml). Diethyl ether (5 ml) was added and the suspension was cooled. After centrifugation, the solvent was removed and the solid was dried, obtaining the target compound in the form of a brown solid (23.5 mg).

C2 ₃ H26 ^ O4 requires 450, M8 (E8 +) m / z 451 (MH ⁺ ).

Example 2. 1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H, 9H-imidazo [ 1,2,3-y] - 1,8-naphthyridine-4,9-dione hydrochloride

(a) N- (6-Chloro-2-pyridinyl) -2,2-dimethylpropanamide.

A solution of 6-chloro-2-pyridinamine (13.776 g, 107 mmol) in toluene (100 ml) and triethylamine (16.28 ml, 118 mmol) was treated with 2,2-dimethylpropanoyl chloride (13.81 ml) at 50 ° C under argon atmosphere. , 112 mmol). The reaction mixture was then stirred at 50 ° C. for 4 hours and then at ambient temperature for 18 hours. Then 2 M HCl (200 ml) was added and the mixture was extracted with diethyl ether (3x500 ml). The organic extracts were dried (Md8O _4), filtered and evaporated to give the product as a brown solid (21.005 g, 92%).

M8 (E8 +) t / ζ 213/215 (MH ⁺ ).

(b) No. (3-Bromo-6-chloro-2-pyridinyl) -2,2-dimethylpropanamide.

A solution of (6-chloro-2-pyridinyl) -2,2-dimethylpropanamide (4.83 g, 22.7 mmol) in THE (40 ml) at -78 ° C in an argon atmosphere was treated with n-butyllithium (20 ml, 2.5 M in hexanes, 50 mmol) for 10 min and then allowed to warm to 0 ° C, stirred at 0 ° C for 3 hours and then re-cooled to -78 ° C. The reaction mixture was then treated by dropwise adding dibromoethane (2.057 ml, 23.9 mmol), the reaction medium was allowed to warm to ambient temperature and stirred at ambient temperature for 0.5 h. The reaction mixture was then treated with water (5 ml), stirred at ambient temperature for 5 min, treated with additional water (500 ml) and extracted with diethyl ether (3x500 ml). The organic extracts were dried (Md8O _4), filtered, evaporated and the residue was chromatographed (0-25% EtOAc: hexane) to give the product as a yellow solid (3.489 g, 53%).

M8 (E8 +) t / ζ 291/293/295 (MH ⁺ ).

(c) No. (3-Bromo-6-chloro-2-pyridinyl) -2,2-dimethyl-No. 2-propen-1-ylpropanamide.

A solution of No. (3-bromo-6-chloro-2-pyridinyl) -2,2-dimethylpropanamide (2.305 g, 7.907 mmol) in IME (40 ml) at 0 ° C under argon was treated with sodium hydride (0.696 g, 17.395 mmol) ) and then allowed to warm to ambient temperature over 0.25 hours, stirred at ambient temperature for 0.25 hours and then treated with allyl iodide (1.61 ml, 17.395 mmol) and stirred at ambient temperature for 1 hour The reaction mixture was then treated with water (10 ml), concentrated to approximately 5 ml, treated with large amounts of water (200 ml) and ext ISM (3x200 ml) were weighed. The organic extracts were dried (Md8O _4), filtered, evaporated and the residue was chromatographed (0-20% EtOAc: hexane) to give the product as a yellow oil which solidified to a solid off-white (5.324 g, 67%).

M8 (E8 +) t / ζ 331/333/335 (MH ⁺ ).

(ά) N- [3-Bromo-6- (methyloxy) -2-pyridinyl] -2,2-dimethyl-# 2-propen-1-ylpropanamide.

A solution of No. (3-bromo-6-chloro-2-pyridinyl) -2,2-dimethyl-No. 2-propen-1-ylpropanamide (12.388 g, 37.370 mmol) in methanol (100 ml) at ambient temperature under argon atmosphere treated with a solution of sodium methylate (25% w / v in methanol, 17.76 g, 82.212 mmol) and then heated under reflux for 42 hours. The reaction mixture was then cooled, treated with water (500 ml) and extracted with diethyl ether (3x200 ml). The organic extracts were dried (MgO ₄ ) and evaporated to give the product (10.918 g, 89%).

M8 (E8 +) t / ζ 327/329 (MH ⁺ ).

(f) No. [3-Bromo-6- (methyloxy) -2-pyridinyl] -№ (2,3-dihydroxypropyl) -2,2-dimethylpropanamide.

A solution of No. [3-bromo-6- (methyloxy) -2-pyridinyl] -2,2-dimethyl-No. 2-propen-1-ylpropanamide (1.246 g, 3.81 mmol) in tert-butanol (40 ml) at ambient temperature in an argon atmosphere was treated with water (40 ml) and then AE-ιηίχ α (2.86 g) and AE-ιηίχ β (2.86 g) and stirred at ambient temperature for 18 hours. The reaction mixture was then treated saturated aqueous sodium sulfite (40 ml), was stirred for 10 min, was extracted with a mixture of 20% methanol / ESM (3x100 ml). The organic extracts were dried (Md8O ₄₎ and evaporated to give crude product (1.728 g, 126%) containing residual tert-butanol.

M8 (E8 +) t / ζ 361/363 (MH ⁺ ).

- 20 015821 (ί) N- [3-Bromo-6- (methyloxy) -2-pyridinyl] -2,2-dimethyl-Y - [(2-oxo-1,3-dioxolan-4-yl) methyl] propanamide.

Solution No. [3-bromo-6- (methyloxy) -2-pyridinyl] -№ (2,3-dihydroxypropyl) -2,2-dimethylpropanamide (7.628 g, 21.130 mmol) in an ESM (100 ml) and pyridine (3.407 ml) , 42.26 mmol) at -78 ° C in an argon atmosphere was treated with a solution of triphosgene (6.27 g, 21.130 mmol) in an ESM (20 ml) for 5 min, the reaction mixture was then allowed to warm to ambient temperature and stirred at a temperature environment for 30 min. The reaction mixture was then carefully treated with saturated solution (200 ml) of sodium bicarbonate, and extracted with an ESM (3x200 ml). The organic extracts were dried (Md8O _4), evaporated and chromatographed (0-50% EtOAc: hexane) to give the product as a white solid (5.722 g, 70%).

M8 (E8 +) t / ζ 387/389 (MH ⁺ ).

(e) (2E) -3- [2 - {(2,2-Dimethylpropanoyl) [(2-oxo-1,3-dioxolan-4-yl) methyl] amino} -6- (methyloxy) -3pyridinyl] - 2-butylpropenoate.

Mixture No. [3-bromo-6- (methyloxy) -2-pyridinyl] -2,2-dimethyl-No. [(2-oxo-1,3-dioxolan-4-yl) methyl] propanamide (5.722 g, 14.722 mmol ), Pb (PbBi ₃ ) ₂ (151 mg, 0.296 mmol), P4 ₂ (4ba) ₃ (135 mg, 0.149 mmol) in 1,4-dioxane (40 ml) was treated with Ν, Ν'-dicyclohexylmethylamine (3.48 ml, 16.265 mmol) and n-butyl acrylate (2.54 ml, 17.743 mmol) and the mixture was then heated at 80 ° C for 1 h. The reaction mixture was then cooled, treated with water (200 ml), and extracted with an ESM (3x200 ml). The organic extracts were dried (Md8O _4), evaporated and chromatographed (0-50% EtOAc: hexane) to give the product as a yellow oil (6.156 g, 96%).

M8 (E8 +) t / ζ 435 (MH ⁺ ).

(11) 3 - [2- {(2,2-Dimethylpropanoyl) [(2-oxo-1,3-dioxolan-4-yl) methyl] amino} -6- (methyloxy) -3pyridinyl] butylpropanoate.

Solution (2E) -3- [2 - {(2,2-dimethylpropanoyl) [(2-oxo-1,3-dioxolan-4-yl) methyl] amino} -6 (methoxy) -3-pyridinyl] -2 -butylpropenoate (6.156 g, 14.184 mmol) in ethanol (200 ml) was treated with palladium-carbon (10% paste, 1.23 g) and the mixture was then stirred at ambient temperature under 1 atm hydrogen for 18 hours. The reaction mixture was then filtered through a thin layer of celite, eluting with an additional amount of ethanol (200 ml). The organic filtrate was then evaporated to give the product in the form of a yellow oil (6.065 g, 98%).

M8 (E8 +) t / ζ 437 (MH ⁺ ).

(ί) 1- (2,3-dihydroxypropyl) -7- (methyloxy) -3,4-dihydro-1,8-naphthyridin-2 (1H) -one.

Solution 3 - [2- {(2,2-dimethylpropanoyl) [(2-oxo-1,3-dioxolan-4-yl) methyl] amino} -6- (methyloxy) -3pyridinyl] butylpropanoate (6.065 g, 13.911 mmol ) in methanol (100 ml) was treated with a concentrated aqueous solution of HCl (12 M, 50 ml) and then heated under reflux for 48 hours. The reaction mixture was then concentrated to approximately 50 ml, neutralized with potassium carbonate and extracted with 20% methanol / ESM. (3x100 ml). The organic extracts were dried (MgO ₄ ) and evaporated to give the crude product in the form of a yellow oil (2.325 g, 66%).

M8 (E8 +) t / ζ 279 (MH ⁺ ).

(ί) 7- (methyloxy) -1- (2-oxiranylmethyl) -3,4-dihydro-1,8-naphthyridin-2 (1H) -one.

Solution of 1- (2,3-dihydroxypropyl) -7- (methyloxy) -3,4-dihydro-1,8-naphthyridin-2 (1H) -one (2.325 g, 9.226 mmol) in ESM (40 ml) and triethylamine (1.915 ml, 13.839 mmol) at 0 ° C in an argon atmosphere was treated with methanesulfonyl chloride (0.714 ml, 9.226 mmol) and stirred at 0 ° C for 0.5 h. The reaction mixture was then treated with water (100 ml), and extracted with an ESM (3x100 ml). The organic extracts were dried (MgSO ₄ ) and evaporated. The residue was then dissolved in methanol (50 ml) and treated with potassium carbonate (6.366 g, 46.130 mmol) and stirred at ambient temperature for 15 minutes. The reaction mixture was then treated with water (100 ml), and extracted with an ESM (3x200 ml). The organic extracts were dried (Md8O _4), evaporated and chromatographed (0-100% ethyl acetate: hexane) to give the product as a yellow oil (428 mg, 20%).

M8 (E8 +) t / ζ 235 (MH ⁺ ).

(k) 1,1 - Dimethylethyl (1 - {2-hydroxy-3- [7- (methyloxy) -2-oxo-3,4-dihydro-1,8-naphthyridin-1 (2H) yl] propyl} - 4-piperidinyl) carbamate.

Solution of 7- (methyloxy) -1- (2-oxiranylmethyl) -3,4-dihydro-1,8-naphthyridin-2 (1H) -one (428 mg, 1.829 mmol) and 1,1-dimethylethyl-4-piperidinylcarbamate (366 mg, 1.829 mmol) in OME (2 ml) under argon was heated at 120 ° C for 1 h. The mixture was then evaporated and chromatographed (0-10% methanol / OCM) to give the product in the form of a yellow oil (301 mg , 38%).

M8 (E8 +) t / ζ 435, (MH ⁺ ).

- 21 015821 (1) 1,1-Dimethylethyl {1 - [(4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-c] -1.8 naphthyridin-2yl) methyl] -4-piperidinyl} carbamate.

Solution 1,1-dimethylethyl (1- {2-hydroxy-3- [7- (methyloxy) -2-oxo-3,4-dihydro-1,8-naphthyridine1 (2H) -yl] propyl} -4-piperidinyl ) carbamate (301 mg, 0.694 mmol) in chloroform (10 ml) and triethylamine (0.24 ml, 1.735 mmol) at ambient temperature under argon atmosphere was treated with methanesulfonic anhydride (242 mg, 1.388 mmol) and heated under reflux in for 2 hours. The reaction mixture was then evaporated and dissolved in acetonitrile (10 ml), treated with sodium iodide (520 mg, 3.47 mmol) and heated at 80 ° C for 0.25 hours. The mixture was then cooled, evaporated, then sampled. batyvali water (200 ml), extracted with 20% methanol / SEM (3x200 mL). The organic extracts were dried (MgSO ₄ ), evaporated and chromatographed (0-10% methanol / OCM) to give the product in the form of an orange oil (194 mg, 70%).

M8 (E8 +) t / ζ 403 (MH ⁺ ).

(t) 1,1-Dimethylethyl {1 - [(4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-g)] - 1,8-naphthyridin-1yl) methyl ] -4-piperidinyl} carbamate.

Solution 1,1-dimethylethyl {1 - [(4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-g)] - 1,8naphthyridin-1-yl ) methyl] -4-piperidinyl} carbamate (194 mg, 0.483 mmol) (301 mg, 0.694 mmol) in 1,4-dioxane (5 ml) was treated with EER (164 mg, 0.724 mmol) and stirred at 60 ° C for 24 hours. An additional amount of EER (164 mg, 0.724 mmol) was added and the reaction mixture was stirred for another 2 hours. The reaction mixture was then treated with 5% aqueous potassium carbonate solution (100 ml), extracted with 20% methanol / OSM (3x200 ml) . The organic extracts were dried (MgO ₄ ) and evaporated to give the product in the form of an orange oil (159 mg, 82%).

M8 (E8 +) t / ζ 401 (MH ⁺ ).

(η) 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-c] - 1,8-naphthyridine-4,9dione dihydrochloride.

Solution 1,1-dimethylethyl {1 - [(4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-g)] - 1,8-naphthyridin-1yl) methyl] - 4-piperidinyl} carbamate (159 mg, 0.398 mmol) in chloroform (2 ml) and methanol (2 ml) in an argon atmosphere at ambient temperature was treated with 4 M HC1 in 1,4-dioxane (2 ml) and stirred at ambient temperature medium for 0.5 h. The reaction mixture was then dried and evaporated to give the product in the form of a yellow solid (138 mg, 93%).

M8 (E8 +) t / ζ 301 (MH ⁺ ).

(o) Target compound.

A mixture of 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-ί)] - 1,8-naphthyridine-4,9dione dihydrochloride (49 mg, 0.131 mmol) in an ESM (2 ml) and methanol (0.1 ml) in an argon atmosphere at ambient temperature was treated with triethylamine (58 μl, 0.419 mmol) and stirred at ambient temperature for 0.25 h, after which [1,3] oxathiolo [5,4s] pyridin-6-carbaldehyde was added (for synthesis see XVO 2004058144, Example 61) (22 mg, 0.131 mmol). The mixture was then stirred at ambient temperature for 1 h, after which ΝαΒ ^ ΟΑο ^ (56 mg, 0.262 mmol) was added. The reaction mixture was stirred at ambient temperature for another 0.5 h, after which a saturated aqueous sodium bicarbonate solution (20 ml) was added. The mixture was extracted with 20% methanol / OCM (3x100 ml). The organic extracts were dried (Md8O _4), evaporated and chromatographed (0-20% methanol / OCM) to give the product as a clear oil (28 mg, 47%).

M8 (E8 +) t / ζ 452 (MH ⁺ ).

Ή NMR (СРС1 ₃ , 400 MHz) δ 1.38-1.48 (2Н, m), 1.78-1.95 (2Н, m), 2.15-2.37 (2Н, m) 2, 45-2.60 (1H, m), 2.61-2.72 (2H, m), 2.92-3.02 (1H, m), 3.05-3.12 (1H, m), 3.83 (2H, s), 4.32-4.42 (1H, m), 4.52-4.61 (1H, m), 4.96-5.05 (1H, m), 5, 74 (2H, s), 6.22-6.32 (2H, m), 7.20 (1H, s), 7.45-7.52 (2H, m), 7.99 (1H, s) .

The free base of the target compound in methanol and chloroform was converted to the hydrochloride by adding the equivalent of 4 M hydrogen chloride in 1,4-dioxane, followed by evaporation to dryness.

Example 3. 1 - ({4 - [(2,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro -4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

Method A.

A mixture of 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-ί)] - 1,8-naphthyridine-4,9dione dihydrochloride (36 mg, 0.0965 mmol) (for preparation see Example 2 (η)) in an ESM (2 ml) and methanol (0.1 ml) in an argon atmosphere at ambient temperature was treated with triethylamine (43 μl, 0.309 mmol) and was stirred at ambient temperature for 0.25 hours, after which 2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-carboxaldehyde was added (for synthesis see νΟ2004058144, example 2 ( c) or νΟ 03/087098, example 19 (ά))) (16 mg, 0.0965 mmol). The mixture is then

- 22 015821 was stirred at ambient temperature for 1 h, after which NaBH (OAc) ₃ (41 mg, 0.193 mmol) was added. The reaction mixture was stirred at ambient temperature for another 0.5 h, after which a saturated aqueous sodium bicarbonate solution (20 ml) was added. The mixture was extracted with 20% methanol / OCM (3x100 ml). The organic extracts were dried (Md8O _4), evaporated and chromatographed (0-20% methanol / OCM) to give the free base of the title compound as a clear oil (24 mg, 55%).

M8 (E8 +) t / ζ 450 (MH ⁺ ).

Ή NMR (SPS1 ₃ , 400 MHz) δ 1.30-1.50 (2H, m), 1.80-1.92 (2H, m), 2.19-2.35 (2H, m) 2, 49-2.72 (3H, m), 2.92-3.02 (1H, m), 3.07-3.13 (1H, m), 3.81 (2H, s), 4.22- 4.51 (5H, m) 4.52-4.60 (1H, m), 4.96-5.04 (1H, m), 6.226.32 (2H, m), 6.81 (1H, s ), 7.45-7.53 (2H, m), 8.04 (1H, s).

The free base of the target compound in methanol and chloroform was converted to the hydrochloride by adding the equivalent of 4 M hydrogen chloride in 1,4-dioxane, followed by evaporation to dryness.

Method B.

(a) 2-Bromo-3 - [(phenylmethyl) oxy] propionic acid.

Racemic O- (phenylmethyl) serine (5 g, 25.6 mmol) and potassium bromide (10.7 g, 89.6 mmol) were dissolved in ice-cold H ₂ 8 O ₄ (2.5 N) and treated with sodium nitrite solution ( 2.65 g) in water (30 ml) for 50 min (maintaining the reaction temperature <4 ° C). The reaction mixture was then stirred at 0 ° C for 45 min, and then at ambient temperature for 1 h, it was extracted with ethyl acetate (3x100 ml). The combined organic extracts were washed with water, brine, dried (MD8O ₄ ), filtered and evaporated to give the product in the form of a yellow oil (6 g, 90%).

M8 (E8 +) t / ζ 259/261 (MH ⁺ ).

(b) 2-Bromo-3 - [(phenylmethyl) oxy] methylpropanoate.

A solution of 2-bromo-3 - [(phenylmethyl) oxy] propionic acid (6 g, 23.2 mmol) in methanol (40 ml) was treated with thionyl chloride (1.7 ml, 23.2 mmol) at ambient temperature under argon atmosphere. and the reaction mixture was then stirred at ambient temperature for 3 hours and then evaporated to give the product in the form of a yellow oil (6.3 g, 99%).

M8 (E8 +) t / ζ 273/275 (MH ⁺ ).

(c) 2- [4 - ((2,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) {[(1,1-dimethylethyl) oxy] carbonyl} amino) - 1-piperidinyl] -3 - [(phenylmethyl) oxy] methylpropanoate.

A mixture of 1,1-dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) -4-piperidinyl carbamate (1.087 g, 3.11 mmol) (for synthesis see XVO 2004/058144, Example 99 (11)). 2-bromo-3 [(phenylmethyl) oxy] methylpropanoate (1.0 g, 3.66 mmol) and potassium carbonate (0.860 g, 6.22 mmol) in OME (50 ml) were heated at 80 ° C and stirred in the atmosphere argon for 2.5 hours. Solvents were removed under reduced pressure and the residue was treated with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with OCM (5x100 ml), dried over Md8O _4, filtered and concentrated under reduced pressure. The crude product was chromatographed, eluting with 0-100% E1OAc / 40-60 petroleum ether. The appropriate fractions were combined and evaporated under reduced pressure. The residue was then dissolved in OSM (50 ml) and washed with water (20 ml). The organic layer was separated, dried over MgSO ₄ and evaporated under reduced pressure to give the product (618 mg, 35% yield).

M8 (E8 +) t / ζ 542 (MH ⁺ ).

(ά) 1,1 - Dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) [1- (2-hydroxy-1 {[(phenylmethyl) oxy] methyl } ethyl) -4-piperidinyl] carbamate.

To a solution of 2- [4 - ((2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) {[(1,1-dimethylethyl) oxy] carbonyl} amino) -1 -piperidinyl] -3 - [(phenylmethyl) oxy] methylpropanoate (618 mg, 1.141 mmol) in dry THE (8 ml) at -78 ° C under an atmosphere of Ar, L1A1H ₄ (1.312 ml, 1.312 mmol) was added dropwise. The reaction mixture was allowed to warm to -10 ° C in 2 hours. The mixture was then stirred at 0 ° C for 2 hours, after which water (0.1 ml) was added, then sodium hydroxide (0.18 ml, 0.360 mmol) and then water (0.2 ml). The mixture was then stirred for another 2 hours at ambient temperature. The resulting mixture was filtered and washed with THE (100 ml). The combined filtrate and washings were evaporated under reduced pressure to give the product (0.519 g, 89% yield).

M8 (E8 +) t / ζ 514 (MH ⁺ ).

(f) 1,1 - Dimethylethyl [1 - (2-chloro-1 - {[(phenylmethyl) oxy] methyl} ethyl) -4-piperidinyl] (2,3-dihydro [1,4] dioxino [2,3 -c] pyridin-7-ylmethyl) carbamate.

Solution 1,1-dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) [1- (2-hydroxy-1 {[(phenylmethyl) oxy] methyl} ethyl ) -4-piperidinyl] carbamate (150 mg, 0.292 mmol) and triethylamine (0.049 ml, 0.350 mmol) in OCM (5 ml) at 0 ° C were treated with methanesulfonyl chloride (0.025 ml, 0.321 mmol). The solution was allowed to warm to ambient temperature and was stirred at this temperature for 1 hour. An additional 0.2 eq. triethylamine and 0.4 eq. methanesulfonyl chloride and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with OSM (20 ml) and treated with water (2 ml). The aqueous layer was extracted with OSM (50 ml). The organic layers were combined and dried over MgSO ₄ , filtered and evaporated under reduced pressure to a crude

- 23 015821 duct (101 mg, 65%), which was used without further purification.

Μ8 (E8 +) t / ζ 532/534 (MH ⁺ ).

(D) 1,1-Dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) [1- (2- [7- (methyloxy) -2oxo-3, 4-dihydro-1,8-naphthyridin-1 (2H) -yl] -1 - {[(phenylmethyl) oxy] methyl} ethyl) -4 piperidinyl] carbamate.

Method 1. The solution of 1,1-dimethylethyl [1- (2-chloro-1 - {[(phenylmethyl) oxy] methyl} ethyl) -4-piperidinyl] (2,3-dihydro [1,4] dioxino [2, 3-c] pyridin-7-ylmethyl) carbamate (101 mg, 0.190 mmol) in ΌΜΕ (10 ml) was added dropwise to a solution of 7- (methyloxy) -3,4-dihydro-1,8-naphthyridin-2 sodium salt (1H) it (33.8 mg, 0.190 mmol) in ΌΜΕ (10 ml) (obtained by adding sodium hydride (9.11 mg, 0.228 mmol) to 7- (methyloxy) -3,4-dihydro-1,8- naphthyridin-2 (1H) -one (33.8 mg, 0.190 mmol) (for the preparation see Example 5 (e)) in ΌΜΕ (10 ml)). The solution was stirred at ambient temperature overnight in an Ar atmosphere. The reaction mixture was then heated to 60 ° C and stirred at that temperature in an Ar atmosphere for 1 h. The reaction mixture was cooled to ambient temperature and additional equivalent sodium hydride (9.11 mg, 0.228 mmol) was added with stirring under argon atmosphere. The reaction mixture was stirred at ambient temperature for 72 hours.

Method 2. Solution of 1,1-dimethylethyl [1- (2-chloro-1 - {[(phenylmethyl) oxy] methyl} ethyl) -4-piperidinyl] (2,3-dihydro [1,4] dioxino [2, 3-c] pyridin-7-ylmethyl) carbamate (343 mg, 0.645 mmol) in ΌΜΕ (10 ml) was added dropwise to a solution of 7- (methyloxy) -3,4-dihydro-1,8-naphthyridin-2 sodium salt (1H) -one (138 mg, 0.774 mmol) (obtained by adding sodium hydride (60%, 38.7 mg, 0.967 mmol) to 7- (methyloxy) -3,4-dihydro-1, 8-naphthyridin-2 ( 1H) -one (138 mg, 0.774 mmol) (for preparation see Example 5 (e)) in ΌΜΕ (10 ml)). The solution was stirred at ambient temperature overnight under argon.

The reaction mixtures of method 1 and method 2 were combined and ΌΜΕ was removed under reduced pressure. The residue was treated with saturated aqueous sodium bicarbonate (10 ml) and water (20 ml) and extracted with ΩΟΜ (3x100 ml). The combined organic layers were dried (Μ§8Θ ₄ ), filtered and removed under reduced pressure. The crude product was chromatographed, eluting with 0-100% EJAc / hexane. The appropriate fractions were combined to give two product loads (charge 1: 167 mg, 38% and (charge 2: lower purity, 78 mg, 18%).

Μ8 (E8 +) t / ζ 674 (MH ⁺ ).

(e) 1,1-Dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) [1- (2-hydroxy-1 - {[7 (methyloxy) - 2-oxo-3,4-dihydro -1,8-naphthyridin-1 (2H) -yl] methyl} ethyl) -4-piperidinyl] carbamate.

Solution 1,1-dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) [1- (2- [7- (methyloxy) 2-oxo-3,4 -dihydro-1,8-naphthyridin-1 (2H) -yl] -1 - {[(phenylmethyl) oxy] methyl} ethyl) -4-piperidinyl] carbamate (167 mg, 0.248 mmol) in ethanol (20 ml) was hydrogenated at a pressure of 1 atm hydrogen for approximately 9 days. The reaction mixture was filtered through celite and washed with ethanol. The combined filtrate and washings were evaporated under reduced pressure to give the product (162 mg, 91%).

Μ8 (E8 +) t / ζ 584 (MH ⁺ ).

(11) 1,1-Dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) {1 - [(4,9-dioxo-1,2,8, 9tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridin-1-yl) methyl] -4-piperidinyl} carbamate.

Solution 1,1-dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) [1- (2-hydroxy-1 - {[7 (methyloxy) -2- oxo-3,4-dihydro -1,8-naphthyridin-1 (2H) -yl] methyl} ethyl) -4-piperidinyl] carbamate (162 mg, 0.278 mmol) in ΩΟΜ (10 ml) in an argon atmosphere was cooled to 0 ° C and was treated with triethylamine (0.046 ml, 0.333 mmol) and methanesulfonyl chloride (0.026 ml, 0.333 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred at this temperature for 1 hour. An additional 1.2 eq. triethylamine (0.046 ml, 0.333 mmol) and methanesulfonyl chloride (0.026 ml, 0.333 mmol) and the solution was stirred at ambient temperature overnight. An additional 1.2 eq. triethylamine (0.046 ml, 0.333 mmol) and methanesulfonyl chloride (0.026 ml, 0.333 mmol) and the solution were heated to 50 ° C for 6 hours. The solution was cooled to ambient temperature, a saturated aqueous NaHCO3 solution (10 ml) was added and the aqueous layer was extracted with 20 % ΜοϋΗ / ΩΟΜ (3x100 ml). The organic phases were combined, dried Μ§8Θ ₄ , filtered and concentrated. The crude product was then chromatographed, eluting with 0-15% Μе ^Н / ^ СΜ. The appropriate fractions were combined and evaporated under reduced pressure to give the product (80 mg, 48%).

Μ8 (E8 +) t / ζ 552 (MH ⁺ ).

(ί) 1,1-Dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) {1 - [(4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridin-1-yl) methyl] -4-piperidinyl} carbamate.

Solution 1,1-dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) {1 - [(4,9-dioxo1,2,8,9-tetrahydro- 4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridin-1-yl) methyl] -4-piperidinyl} carbamate (80 mg, 0.145 mmol) and ΩΩΟ (49.4 mg, 0.218 mmol ) in 1,4-dioxane (5 ml) was stirred at 120 ° C. for 2 hours. An additional 0.5 eq. ΩΩΟ (17 mg) and the solution were stirred for another 2 hours. The mixture was allowed to cool to ambient temperature and treated with sat. Ν; · ιΗΟΘ ₃ , (10 ml). The aqueous layer was extracted with 20% ΜοϋΗ / ΩΟΜ (3x100 ml). The organic layers were combined, dried Μ§8Θ ₄ ,

24 015821 was filtered and concentrated to give a crude product (64 mg, 83%).

M8 (E8 +) w / ζ 550 (MH ⁺ ).

(ί) Target connection.

Solution 1,1-dimethylethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) {1 - [(4,9-dioxo-1,2-dihydro-4H, 9H- imidazo [1,2,3-y] -1,8-naphthyridin-1-yl) methyl] -4-piperidinyl} carbamate (64 mg,

0.116 mmol) in ESM (2 ml) and HCl in 1,4-dioxane (0.291 ml, 1.164 mmol) was stirred at ambient temperature for 2 hours. Solvents were removed under reduced pressure. The crude product was added to the ion exchange column and MeOH (20 ml) was then eluted and then 2 M N43 in MeOH (15 ml) to give the free base of the target compound (34 mg, 65%).

¹ H NMR and bC-M8 identical to the product of example 3A.

The free base of the target product was then converted to the HC1 salt, dissolved in an ESM (2 ml) and treated with 1 equiv. 1 M HC1 in ether. Solvents were removed under reduced pressure to give the desired hydrochloride.

Example 4. 1 - ({4 - [(7-Bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) amino] -1 piperidinyl } methyl) -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

A mixture of 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-C] - 1,8-naphthyridine-4,9dione dihydrochloride (51 mg , 0.136 mmol) (for preparation see Example 2 (p)) in an ESM (2 ml) and methanol (0.1 ml) in an argon atmosphere at ambient temperature was treated with triethylamine (60 μl, 0.438 mmol) and stirred at a temperature environment for 0.25 hours, after which 7-bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxaldehyde was added (in relation to synthesis see \ UO 2002056882, example 33 (e)) (37 mg, 0.136 mmol). The mixture was then stirred at ambient temperature for 1 h, after which NaBH (OAc) s (86 mg, 0.408 mmol) was added. The reaction mixture was stirred at ambient temperature for another 0.5 h, after which a saturated aqueous sodium bicarbonate solution (20 ml) was added. The mixture was extracted with 20% methanol / ESM (3x100 ml). The organic extracts were dried (Md8O _4), evaporated and chromatographed (0-20% methanol / OCM) to give the free base of the title compound as a clear oil (36 mg, 48%).

M8 (E8 +) w / ζ 558 (MH ⁺ ).

Ή NMR (SSC1 ₃ , 400 MHz) δ 1.32-1.51 (2H, m), 1.81-2.00 (2H, m), 2.20-2.41 (2H, m) 2, 50-2.75 (3H, m), 2.93-3.03 (1H, m), 3.04-3.15 (1H, m), 3.46 (2H, s), 3.98 ( 2H, s), 4.32-4.41 (1H, m) 4.52-4.61 (1H, m), 4.98-5.04 (1H, m), 6.22-6.32 (2H, m), 7.48-7.51 (2H, m), 7.75 (1H, s).

The free base in methanol and chloroform was converted to the desired hydrochloride salt by adding the equivalent of 4 M hydrogen chloride in 1,4-dioxane, followed by evaporation to dryness.

Example 5A (1H) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

(a) 2,2-Dimethyl-No. [6- (methyloxy) -2-pyridinyl] propanamide.

Suspension of trimethylacetamide (18.08 g, 178.744 mmol), Cg ₂ CO ₃ (68.823 g, 211.242 mmol), Pb ₂ (ba) ₃ (1.488 g, 1.625 mmol) and Hapfock (4,5-bis (diphenylphosphino) -9.9-dimethylxanthene) (1.880 g, 3.249 mmol) in dry degassed 1,4-dioxane (800 ml) under argon was sonicated for 0.25 hours and then treated with 2-chloro-6- (methyloxy) pyridine (19.32 ml, 162.494 mmol). The mixture was then refluxed for 24 hours. The mixture was evaporated, treated with water (1 L) and extracted with 3x ESM (1 L and then 2x500 ml). The organic extracts were dried (Md8O _4), evaporated and chromatographed (50-100% OCM / 40-60 Petroleum ether then 0-5% methanol / OCM) to give the title compound as a yellow solid (25.191 g, 121.111 mmol, 75%). The crude fractions were rechromatographed (eluting as above) to give an additional amount of product (4.990 g, 23.990 mmol, 15%). Full yield 90%.

M8 (E8 +) w / ζ 209 (MH ⁺ , 100%).

25 015821 (b) Y- [3-Bromo-6- (methyloxy) -2-pyridinyl] -2,2-dimethylpropanamide.

A solution of 2,2-dimethyl-L- [6- (methyloxy) -2-pyridinyl] propanamide (55.011 g, 264.467 mmol) in TNB (450 ml) in a 1 L three-necked flask with an internal thermometer in an argon atmosphere was cooled to -78 ° C and treated with n-butyllithium (232 ml, 581.847 mmol) for 15 minutes and then allowed to warm to 0 ° C and stirred at 0 ° C for 7 hours. The mixture was then re-cooled to -78 ° C and treated

1,2-dibromoethane (27.3 ml, 317 mmol) for 10 minutes and then the solution was allowed to warm to ambient temperature and stirred at ambient temperature for 30 minutes, during which all the solid formed was dissolved again. At this stage, gas was formed, so a gas bubbler was placed on one of the neck of the flask. Then, over 10 minutes, water (100 ml) was carefully added. Then, additional water (500 ml) was added and the mixture was extracted with diethyl ether (3x500 ml). The combined organic solvents were then dried (MgSO ₄ ), filtered, evaporated to give a crude product. Then it was dissolved in warm ethyl acetate (100 ml) and left in the freezer overnight. The resulting solid that crystallized was filtered off, washed with ice-cold diethyl ether (20 ml) and dried in vacuo to give the product in the form of a white solid (45.660 g, 159.011 mmol, 60% yield). The filtrate was evaporated and the residue was chromatographed (0-25% ethyl acetate / 40-60 petroleum ether) to obtain a recovered starting material (7.264 g, 34.9 mmol) and the product in the form of a white solid (8.038 g, 27.992 mmol, 10% - exit). Products from recrystallization and chromatography on silica gel were identical in their NMR and BS-M8 and therefore they were combined.

M8 (E8 +) t / ζ 287/289 (MH ⁺ , 100%).

(c) (2E) -3- [2 - [(2,2-Dimethylpropanoyl) amino] -6- (methyloxy) -3-pyridinyl] -2-butylpropenoate.

A mixture of Y- [3-bromo-6- (methyloxy) -2-pyridinyl] -2,2-dimethylpropanamide (78.783 g, 274 mmol), bis- (tris-tert-butylphosphine) palladium (0) (1 g, 1.957 mmol) and tris- (dibenzylideneacetone) dipalladium (0) (0.892 g, 0.974 mmol) in dry degassed 1,4-dioxane (600 ml) were treated with n-butyl acrylate (47.1 ml, 329 mmol) and dicyclohexylmethylamine (64.5 ml, 302 mmol). The reaction mixture was then heated at 80 ° C. for 4 hours and then at 120 ° C. for 3 hours. The reaction mixture was then evaporated, water (1000 ml) was added and the mixture was extracted with diethyl ether (3x500 ml). The combined organic solvents were then dried (MgSO ₄ ), filtered, evaporated to give a crude product. It was then dissolved in an ESM (300 ml) and chromatographed (10-30% ethyl acetate: 40-60 petroleum ether) and then dried in vacuo to give the product in the form of a white solid (87.412 g, 95%).

M8 (E8 +) t / ζ 335 (MH ⁺ , 100%).

(b) 3- [2 - [(2,2-Dimethylpropanoyl) amino] -6- (methyloxy) -3-pyridinyl] butylpropanoate.

A solution of (2E) -3- [2 - [(2,2-dimethylpropanoyl) amino] -6- (methyloxy) -3-pyridinyl] -2-butylpropenoate (43,706 g, 131 mmol) in ethanol (450 ml) in the atmosphere argon at ambient temperature was treated with palladium on charcoal (5.0 g, 47.0 mmol) and then stirred at ambient temperature under 1 atm of hydrogen for 90 hours. The reaction mixture was then filtered through a thin layer of Kieselguhr, washing off the product with additional ethanol (200 ml). The solvent was then evaporated to give the product in the form of a yellow oil (43.549, 99%).

M8 (E8 +) t / ζ 337 (MH ⁺ , 100%).

(e) 7- (methyloxy) -3,4-dihydro-1,8-naphthyridin-2 (1H) -one.

A mixture of 3- [2 - [(2,2-dimethylpropanoyl) amino] -6- (methyloxy) -3-pyridinyl] butylpropanoate (86.01 g, 256 mmol) in hydrochloric acid (500 ml, 3000 mmol) (6 M aqueous solution) was heated at 80 ° C for 6 h. The reaction mixture was cooled, treated with water (500 ml), placed in a 5-liter conical flask and carefully neutralized with solid potassium carbonate (about 250 g) (active boiling was observed). The mixture was then extracted with 20% MeOH / OCM (3x500 ml). The combined organic solvents were then dried (Md8O _4), filtered and evaporated to give crude product in the form of a yellow solid (35.84 g, 79%).

M8 (E8 +) t / ζ 179 (MH ⁺ , 100%).

(1) 7- (methyloxy) -1 - [(2K) -2-oxiranylmethyl] -3,4-dihydro-1,8-naphthyridin-2 (1H) -one.

A solution of 7- (methyloxy) -3,4-dihydro-1,8-naphthyridin-2 (1H) it (4.974 g, 27.9 mmol) in OME (100 ml) at 0 ° C under argon was treated with sodium hydride ( 60%, 1.340 g, 33.5 mmol) and stirred at 0 ° C for 20 minutes. The reaction mixture was then treated with (28) -2-oxiranylmethyl-3 nitrobenzenesulfonate (7.60 g, 29.3 mmol), stirred at 0 ° C and then allowed to warm to ambient temperature and stirred at ambient temperature for 1 hour. Then water (5 ml) was added. The reaction mixture was evaporated, then a saturated aqueous bicarbonate solution (500 ml) was added and the mixture was extracted with ESM (3x500 ml). The combined organic solvents were then dried (Md8O _4), filtered and evaporated to give crude product.

M8 (E8 +) t / ζ 235 (MH ⁺ , 100%).

- 26 015821 (d) (18) -1- (Hydroxymethyl) -1,2,5,6-tetrahydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9 Dion.

Solution of 7- (methyloxy) -1 - [(2K) -2-oxiranylmethyl] -3,4-dihydro-1,8-naphthyridin-2 (1H) she (1.167 g, 4.98 mmol) in ΌΜΡ (20 ml ) in an argon atmosphere was heated at 120 ° C for 6 hours. The reaction mixture was then evaporated and chromatographed (0-20% methanol / ESM) to give the product as an orange solid (339 mg, 31%).

M8 (E8 +) t / ζ 221 (MH ⁺ , 100%).

Alternatively, the reaction mixture may be heated in a microwave reactor at 160 ° C. for 40 minutes.

(i) 1,1-Dimethylethyl (1 - {[(2K) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1, 8-naphthyridin-2-yl] methyl} -4-piperidinyl) carbamate.

Solution (18) -1- (hydroxymethyl) -1,2,5,6-tetrahydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9dione (1,909 g, 8 , 67 mmol) in an ISM (100 ml) at 0 ° C in an argon atmosphere was treated with triethylamine (1.450 ml, 10.40 mmol) and then methanesulfonyl chloride (0.743 ml, 9.54 mmol) and then allowed to warm to ambient temperature and stirred at ambient temperature for 1 h. The reaction mixture was then treated with saturated aqueous bicarbonate (100 ml) and the mixture was extracted with ISM (2x100 ml). The combined organic solvents were then dried (Md8O _4), filtered and evaporated to give the crude intermediate [(28) -4,9-dioxo-1,2,8,9tetragidro-4H, 7H-imidazo [1,2,3-y ] -1,8-naphthyridin-2-yl] methyl methanesulfonate, It was dissolved in dry acetonitrile (100 ml) and then treated with pyridine (1.402 ml, 17.34 mmol) and 1,1-dimethylethyl-4-piperidinyl carbamate (3.47 g , 17.34 mmol) and heated at 70 ° C for 20 hours. After 20 hours, an additional amount of 1,1-dimethylethyl-4-piperidinyl carbamate (3.47 g, 17.34 mmol) and pyridine (1.402 ml, 17) were added. , 34 mmol), temperature increased wali to reflux (heating block 95 ° C) and the reaction mixture was stirred at this temperature for a further 4 hours. The reaction mixture was then evaporated, followed by addition of a saturated aqueous solution NaΗSOz (200 ml) and the mixture was extracted with IMS (3x200 mL). The combined organic solvents were then dried (MgSO ₄ ), filtered and evaporated to give the crude product in the form of a brown solid.

M8 (E8 +) t / ζ 403 (MH ⁺ , 100%).

(ί) 1,1-Dimethylethyl (1 - {[(1K) -4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine- 1yl] methyl} -4-piperidinyl) carbamate.

Solution 1,1-dimethylethyl (1 - {[(2K) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8naphthyridine- 2-yl] methyl} -4-piperidinyl) carbamate (5.710 g, 14.19 mmol) in 1,4-dioxane (50 ml) was treated with ΩΩΟ (4.83 g, 21.28 mmol) at ambient temperature and then heated at 120 ° C. for 1 h. The reaction mixture was then cooled to ambient temperature. The reaction mixture was treated with a saturated aqueous solution of K ₂ CO ₃ (5%, 1000 ml) and was extracted with ISM (3x500 ml). The combined organic solvents were then dried (MgSO ₄ ), filtered and evaporated to give the crude product in the form of a brown solid. The reaction was repeated using an additional portion of carbamate (2.889 g, 7.18 mmol) in 1,4-dioxane (50 ml) with ΩΩΟ (2.444 g, 10.77 mmol). The reaction was carried out and the treatment was carried out as described above, and the combined residues were chromatographed (0-100% ethyl acetate: 40-60 petroleum ether, then 0-20% methanol: ethyl acetate) to obtain the product in the form of a brown solid (1.532 g).

M8 (E8 +) t / ζ 401 (MH ⁺ , 100%).

(ί) (1K) -1 - [(Amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9dion dihydrochloride.

Solution 1,1-dimethylethyl (1 - {[(1K) -4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine1-yl] methyl} -4-piperidinyl) carbamate (1.532 g, 3.83 mmol) in chloroform (20 ml) in an argon atmosphere at ambient temperature was treated with 4 M HC1 in 1,4-dioxane (10 ml, 40.0 mmol) and stirred at ambient temperature for 0.25 hours. Then methanol (20 ml) was added and the reaction mixture was stirred for another 0.25 hours. The reaction mixture was then evaporated and triturated with diethyl ether (20 ml). The solid was then dried in vacuo to give the crude product in the form of a brown solid (1.443 g, 101%).

M8 (E8 +) t / ζ 301 (MH ⁺ , 100%).

1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione dihydrochloride obtained by this general method (Example 5 (a) - (C), a chiral HPLC was analyzed (CyclArak A8-H (5 μm) and it was found to be the only enantiomer, presumably K.

(k) Target compound.

Suspension of (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8naphthyridine-4,9-dione dihydrochloride (crude product) (575 mg, 1.540 mmol) in chloroform (20 ml) and methanol (1 ml) at ambient temperature under argon was treated with triethylamine (0.644 ml, 4.62 mmol) and stirred at ambient temperature for 0.25 h. The solution was then treated with [1,3] oxathiolo [5,4-c] pyridin-6-carbaldehyde (in relation to synthe

- 27 015821 per cm \ νϋ 2004058144, example 61) (258 mg, 1.540 mmol) and was stirred for another 0.5 hours. The solution was then treated with No. 1ВН (ОЛе) ₃ (979 mg, 4.62 mmol) and stirred at a temperature environment for 0.5 h. The reaction mixture was then treated with saturated aqueous solution No. ₁ HCO ₃ (100 ml) and was extracted with a mixture of 20% methanol / ESM (3x200 ml). The combined organic extracts were dried (MgSO ₄ ), filtered, evaporated and chromatographed (0-20% methanol / OCM) to give the free base of the target compound as a light brown solid (574 mg, 1.273 mmol, 83%).

Ή NMR (SPS1 ₃ , 250 MHz) δ 1.25-1.45 (2Н, m), 1.75-1.95 (2Н, m), 2.20-2.45 (2Н, m), 2 45-2.55 (1H, m), 2.60-2.75 (2H, m), 2.90-3.00 (1H, m), 3.05-3.15 (1H, dd) 3.85 (2H, s), 4.30-4.40 (1H, m), 4.55-4.65 (1H, m), 4.95-5.05 (1H, m), 5 75 (2H, s), 6.25 (1H, m), 6.30 (1H, m), 7.20 (1H, s), 7.45-7.52 (2H, m), 8, 00 (1H, s).

Mg (E8 +) t / ζ 452 (MH ⁺ ).

The free base in ESM / MeOH 2: 1 (15 ml) was treated with 1 M HC1 in diethyl ether and then evaporated to give the desired hydrochloride.

Example 5B (1K) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione benzoate.

(1K) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridin-4,9-dione was dissolved in methanol and treated with benzoic acid (1 equiv.). Concentration, treatment with diethyl ether and evaporation of the solvents under reduced pressure gave the product in the form of benzoate.

Example 5C. (1 K.) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione dithrifluoroacetate.

(1K) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a , 5,8a-triazacenaphthylene-3,8-dione hydrochloride in the eluent [10% MECA in water (TEL content 0.1%)] was applied to a reverse phase preparative HPLC column. Product-containing fractions were combined, concentrated, and the concentrate was lyophilized. The product was isolated in the form of a sticky white foam after drying (over the weekend) over P2O5.

Example 6A (1K) -1 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1 piperidinyl} methyl) -1,2-dihydro 4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9-dione hydrochloride

Suspension (1 G) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8naphthyridine-4,9- dione dihydrochloride (511 mg, 1.399 mmol) (for preparation see Example 5 (])) in chloroform (20 ml) and methanol (1 ml) at ambient temperature under argon atmosphere was treated with triethylamine (0.572 ml, 4.11 mmol) ) and stirred at ambient temperature for 0.25 hours. The solution was then treated with 2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-carbaldehyde (for synthesis see νθ 2004058144, example 60) (248 mg, 1.389 mmol) and stirred for another 0.5 hours. The solution was then treated ali No. 1BH (OLe) ₃ (870 mg, 4.11 mmol) and stirred at ambient temperature for 0.5 h. The reaction mixture was then treated with saturated aqueous NaHCO ₃ solution (100 ml) and extracted with 20% methanol / ESM (3x200 ml). The combined organic extracts were dried (MgSO ₄ ), filtered, evaporated and chromatographed (0-20% methanol / ESM) to give the free base of the title compound as a light brown solid (499 mg, 78%).

Mg (E8 +) m / z 466 (MH ⁺ ).

Ή NMR (SPS1 ₃ , 250 MHz) δ 1.21-1.48 (2Н, m), 1.72-1.92 (2Н, m), 2.12-2.39 (2Н, m) 2, 41-2.78 (3H, m), 2.89-3.22 (4H, m), 3.78 (2H, s), 4.28-4.48 (3H, m) 4.50-4 61 (1H, m), 4.96-5.04 (1H, m), 6.19-6.32 (2H, m), 7.01 (1H, s), 7.42-7.53 (2H, m), 8.00 (1H, s).

The free base in ESM / Meon 2: 1 (15 ml) was treated with 1 equiv. 1 M HC1 in diethyl ether and then evaporated to give the desired hydrochloride.

Example 6B (1G) -1 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1 piperidinyl} methyl) -1,2-dihydro 4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9-dione hydrochloride.

(1K) -1 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione was dissolved in methanol and treated with benzoic acid (1 equiv.). Evaporation of the solvents under reduced pressure gave the product in the form of benzoate.

Example 6C (1K) -1 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2- dihydro-4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9-dione dithrifluoroacetate.

(1K) -1 - ({4 - [([1,3] Oxathiolo [5,4-e] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a , 5,8a-triazacenaphthylene-3,8-dione hydrochloride was applied to a reverse phase preparative HPLC column in a mixture of 10% MECA in water containing 0.1% TEM. Product fractions containing

- 28 015821 united, concentrated and the concentrate was lyophilized. The product (bis-TEM salt) was isolated in the form of a white solid after drying over P2O5.

Example 7. (1H) -1 - ({4 - [(5,6,7,8-Tetrahydro-3-isoquinolinylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

(a) 5,6,7,8-Tetrahydro-3-isoquinolinethyl carboxylate.

A solution of 1,7-octadiin (4.00 ml, 30.1 mmol) and ethyl cyanoformate (2.95 ml, 30.1 mmol) in dry degassed 1,4-dioxane (500 ml) in an argon atmosphere was treated at ambient temperature cyclopentadienyl-cobaltf-dicarbonyl (0.814 g, 4.52 mmol) and then refluxed for 18 hours. The reaction mixture was then evaporated, treated with toluene (100 ml), evaporated a second time, dissolved in an ESM (100 ml), filtered through a thin layer of Kieselguhr, eluting with PCM, the organic extracts were evaporated, chromatographed (0-100% ESM: 40-60 petroleum ether, I use 0-10% methanol / OSM) to obtain the product in the form of a crude brown oil (1.27 g, 21%).

M8 (E8 +) t / ζ 206 (MH ⁺ ).

(b) 5,6,7,8-Tetrahydro-3-isoquinolinylmethanol.

A solution of 5,6,7,8-tetrahydro-3-isoquinolinethyl carboxylate (1.27 g, 6.19 mmol) in THE (50 ml) at -78 ° C in an argon atmosphere was treated with L1A1H ₄ (1 M solution in THE, 6 , 19 ml, 6.19 mmol) and allowed to warm to ambient temperature. After 10 min at ambient temperature, water (1 ml), 2 M aqueous solution No. 1OH (1 ml) and water (1 ml) were successively added, and the mixture was stirred at ambient temperature for 0.5 h. The mixture was then filtered through a thin Kieselguhr layer, eluting with TUE (50 ml), the organic extracts were then evaporated, chromatographed (0-20% methanol / OSM) to give the product in the form of an orange oil (0.572 g, 57%).

M8 (E8 +) t / ζ 164 (MH ⁺ ).

(c) 5,6,7,8-Tetrahydro-3-isoquinoline carboxaldehyde.

A solution of 5,6,7,8-tetrahydro-3-isoquinolinylmethanol (572 mg, 3.50 mmol) in (ESM) (10 ml) was treated with manganese dioxide (3.047 g, 35.0 mmol) at ambient temperature under argon atmosphere. and then stirred at ambient temperature for 2 hours. The reaction mixture was then filtered through a thin layer of Kieselguhr, eluting with ESM (50 ml), the organic extracts were evaporated to give the crude product in the form of a brown oil (435 mg, 77%).

M8 (E8 +) t / ζ 162 (MH ⁺ ).

(i) Target compound /

Suspension (1H) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8naphthyridine-4,9-dione dihydrochloride (87 mg, 0.233 mmol) (for preparation see example 5 (])) in chloroform (5 ml) and methanol (0.2 ml) at ambient temperature under argon atmosphere was treated with triethylamine (97 μl, 0.699 mmol) and stirred at ambient temperature for 0.25 hours. The solution was then treated with 5,6,7,8-tetrahydro-3-isoquinolinecarbaldehyde (37.6 mg, 0.233 mmol) and stirred for another 0.5 hours. The solution was then treated with NaH (ОΑс) s (148 mg, 0.699 mmol) and stirred while ambient temperature for 0.5 h. The reaction mixture was then treated with saturated aqueous NaHCO3 (100 ml) and extracted with 20% methanol / ESM (3x200 ml). The combined organic extracts were dried (MgSO ₄ ), filtered, evaporated and chromatographed (0-20% methanol / ESM) to give the free base of the title compound as a pale brown solid (66 mg, 64%).

M8 (E8 +) t / ζ 446 (MH ⁺ ).

Ή NMR (СРС1 ₃ , 250 MHz) δ 1.22-1.51 (2Н, m), 1.71-1.99 (7Н, m), 2.15-2.38 (2Н, m) 2, 45-2.82 (4H, m), 2.61-3.22 (4H, m), 3.85 (2H, s), 4.29-4.42 (1H, m), 4.50- 4.61 (1H, m), 4.96-5.04 (1H, m), 6.18-6.32 (2H, m), 7.00 (1H, s), 7.47-7, 59 (2H, m), 8.21 (1H, s).

The free base in ESM / Meon 2: 1 (15 ml) was treated with 1 equiv. 1 M HC1 in diethyl ether and then evaporated to give the desired hydrochloride.

Example 8. (1H) -1 - ({4 - [(6,7-Dihydro-5H-cyclopenta [c] pyridin-3-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro-4H , 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

(a) 6,7-dihydro-5H-cyclopenta [c] pyridin-3-ethylcarboxylate.

A solution of 1,6-heptadiine (1.242 ml, 10.85 mmol) and ethyl cyanoformate (1.063 ml, 10.85 mmol) in dry degassed 1,4-dioxane (100 ml) in an argon atmosphere at ambient temperature was treated with cyclopentadienyl-cobaltf- dicarbonyl (0.293 g, 1.628 mmol) and then heated to about

- 29 015821 by a reflux condenser for 18 hours. The reaction mixture was then evaporated. treated with toluene (100 ml). evaporated again. dissolved in ESM (100 ml). filtered through a thin layer of Kieselguhr. eluting ESM. the organic extracts were evaporated. chromatographed (0-100% ESM: 40-60 petroleum ether. then 0-10% methanol / OSM). receiving the product in the form of a crude brown oil (427 mg. 21%).

M8 (E8 +) t / ζ 192 (MH ⁺ ).

(b) 6.7-Dihydro-5H-cyclopenta [c] pyridin-3-ylmethanol.

A solution of 6.7-dihydro-5H-cyclopenta [s] pyridin-3-ethylcarboxylate (427 mg. 2.233 mmol) in (ΤΗΕ) (20 ml) at -78 ° C in an argon atmosphere was treated with ΕίΑ1Η ₄ (1 M in ΤΗΕ) (2.233 ml.2.233 mmol) and allowed to warm to ambient temperature. After 10 minutes at ambient temperature, water (1 ml) was added sequentially. A 2 M aqueous solution No. 1OCH (1 ml) and water (1 ml) and the mixture was stirred at ambient temperature for 0.5 h. The mixture was then filtered through a thin layer of Kieselguhr. eluting ΤΗΕ (50 ml). the organic extracts were then evaporated. chromatographed (0-20% methanol / OSM). receiving the product in the form of an orange oil (189 mg. 57%).

M8 (E8 +) t / ζ 150 (MH ⁺ ).

(c) 6.7-Dihydro-5H-cyclopenta [c] pyridin-3-carbaldehyde.

A solution of 6.7-dihydro-5H-cyclopenta [c] pyridin-3-ylmethanol (189 mg. 1.267 mmol) in an ESM (10 ml) at ambient temperature under argon atmosphere was treated with manganese dioxide (1.101 g. 12.67 mmol) and then stirred at ambient temperature for 2 hours, filtered through a thin layer of Kieselguhr. eluting ESM (40 ml). the organic extracts were evaporated. obtaining the crude product in the form of a brown oil (110 mg. 59%).

M8 (E8 +) t / ζ 148 (MH ⁺ ).

(ά) Target connection.

Suspension (1H) -1 - [(4-amino-1-piperidinyl) methyl] -1.2-dihydro-4H.9H-imidazo [1.2.3-y] -1.8 naphthyridine-4.9-dione dihydrochloride (82 mg. 0.220 mmol ) (for the preparation see Example 5 (])) in chloroform (5 ml) and methanol (0.2 ml) at ambient temperature in an argon atmosphere was treated with triethylamine (92 μl. 0.659 mmol) and stirred at ambient temperature for 0.25 h. The solution was then treated with 6.7-dihydro-5H-cyclopenta [s] pyridine-3-carbaldehyde (32.3 mg. 0.220 mmol) and stirred for another 0.5 hours. The solution was then treated with NaΒΗ (ОΑс) s (140 mg. 0.659 mmol) and stirred. at ambient temperature for 0.5 h. The reaction mixture was then treated with a saturated aqueous solution of NaΗCO3 (100 ml) and extracted with a mixture of 20% methanol / OCM (3 × 200 ml). The combined organic extracts were dried (MD8O ₄ ). filtered. evaporated and chromatographed (0-20% methanol / ESM). obtaining the free base of the target compound in the form of a light brown solid (39 mg. 41%).

M8 (E8 +) t / ζ 432 (MH ⁺ ).

Ή NMR (СОС1 _3. 250 MHz) δ 1.32-1.59 (2Η. M). 1.82-2.40 (6N.m). 2.51-2.72 (3N.m). 2.82-3.18 (6N.m).

3.95 (2H, s). 4.31-4.42 (1N.m). 4.50-4.61 (1N.m). 4.92-5.08 (1N.m). 6.19-6.32 (2H. M). 7.23 (1H. S). 7.42-7.53 (2H. M). 8.38 (1H. S).

The free base in ESM / MeOI 2: 1 (15 ml) was treated with 1 equiv. 1 M ΗΟ in diethyl ether and then evaporated. getting the target hydrochloride.

Example 9. (1 I) -1 - ({4 - [(1.3-Dihydrofuro [3.4-s] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-4H.9H-imidazo [1.2.3-y] -1.8-naphthyridine-4.9-dione hydrochloride o, (a) 1.3-dihydrofuro [3.4-c] pyridin-6-ethylcarboxylate.

A solution of di-2-propin-1-yl ester (5.01 g. 53.2 mmol) and ethyl cyanoformate (5.21 ml. 53.2 mmol) in dry degassed 1.4-dioxane (500 ml) in an argon atmosphere at ambient temperature was treated with cyclopentadienyl-cobaltSC-dicarbonyl (1.437 g. 7.98 mmol) and then heated under reflux (heating block 120 ° C) for 18 hours. The reaction mixture was evaporated. treated with toluene (100 ml). evaporated a second time. dissolved in ESM (100 ml). filtered through a thin layer of Kieselguhr. eluting ESM. the organic extracts were evaporated. chromatographed (0-100% 0CM: 40-60 petroleum ether. then 0-10% methanol / ESM). obtaining the product in the form of a brown crude solid (0.871 g) and the crude product in the form of a black oil (2.684 g). which was chromatographed again (0-10-10% methanol / OSM). receiving additional material in the form of a brown solid (1.261 g). The total product obtained was (2.132, 21%).

M8 (E8 +) t / ζ 194 (MH ⁺ ).

- 30 015821 (b) 1,3-dihydrofuro [3,4-c] pyridin-6-ylmethanol.

A solution of 1,3-dihydrofuro [3,4-c] pyridin-6-ethylcarboxylate (0.871 g, 4.51 mmol) in THE (20 ml) at -78 ° C in an argon atmosphere was treated with L1A1H ₄ (1 M in THE) (4.51 ml, 4.51 mmol) and allowed to warm to ambient temperature. After 10 min at ambient temperature, water (1 ml), 2 M aqueous NaOH solution (1 ml) and water (1 ml) were successively added and the mixture was stirred at ambient temperature for 0.5 h. The mixture was then filtered through a thin layer Kieselguhr, eluting with TUE (50 ml), the organic extracts were then evaporated, chromatographed (0-20% methanol / OSM) to give the product in the form of an orange oil (66 mg, 10%).

M8 (E8 +) t / ζ 152 (MH ⁺ ).

(c) 1,3-dihydrofuro [3,4-c] pyridin-6-carbaldehyde.

A solution of 1,3-dihydrofuro [3,4-c] pyridin-6-ylmethanol (66 mg, 0.437 mmol) in an ESM (5 ml) was treated with manganese dioxide (380 mg, 4.37 mmol) at ambient temperature under argon atmosphere. and then stirred at ambient temperature for 2 hours, filtered through a thin layer of Kieselguhr, eluting with ESM (40 ml) and methanol (10 ml), the organic extracts were evaporated to give the crude product in the form of a brown oil (65 mg, 100%).

M8 (E8 +) t / ζ 150 (MH ⁺ ).

(ά) Target connection.

Suspension (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8naphthyridine-4,9-dione (121 mg, 0.324 mmol) (for preparation see Example 5 (])) in chloroform (5 ml) and methanol (0.2 ml) at ambient temperature under argon atmosphere was treated with triethylamine (0.136 ml, 0.972 mmol) and stirred at ambient temperature for 0.25 hours. The solution was then treated with 1,3-dihydrofuro [3,4-c] pyridin-6-carbaldehyde (48.3 mg, 0.324 mmol) and stirred for another 0.5 hours. Solution then treated YaVN (OAc) ₃ (206 mg, 0.972 mmol) and stirred at a temperature of okra ayuschey medium for 0.5 hours. The reaction mixture was then treated with saturated aqueous YaNSO ₃ (100 mL) and extracted with 20% methanol / OSM (3x200 mL). The combined organic extracts were dried (Md8O _4), filtered, evaporated and chromatographed (0-20% methanol / OCM) to give the free base of the title compound as a solid light brown (37 mg, 26%).

M8 (E8 +) t / ζ 434 (MH ⁺ ).

Ή NMR (SPS1 ₃ , 250 MHz) δ 1.21-1.52 (2Н, m), 1.78-2.00 (2Н, m), 2.15-2.40 (2Н, m), 2 49-3.15 (5H, m),

3.95 (2H, s), 4.31-4.48 (1H, m), 4.50-4.62 (1H, m), 4.92-5.19 (5H, m), 6, 19-6.32 (2H, m), 7.27 (1H, s), 7.41-7.54 (2H, m), 8.45 (1H, s).

The free base in ESM / Meon 2: 1 (15 ml) was treated with 1 equiv. 1 M HC1 in diethyl ether and then evaporated to give the desired monosol.

Example 10. (1K) -1 - ({4 - [(3,4-Dihydro-2H-pyrano [2,3-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 -dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

Suspension of (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8naphthyridine-4,9-dione (for production see Example 5 (])) (51 mg, 0.14 mmol) in a mixture of chloroform: methanol (9: 1, 3 ml) at ambient temperature under argon atmosphere was treated with triethylamine (0.06 ml) and stirred at ambient temperature for 10 minutes The solution was then treated with 3,4-dihydro-2H-pyrano [2,3-c] pyridine-6-carbaldehyde (for synthesis see \ UO 2004058144, example 126 (e)) (21 mg, 0.133 mmol) and stirred 2 hours. The solution was then treated with No. 1BH (OAc) ₃ (87 mg) and stirred at ambient temperature for 2 hours. The reaction mixture was then treated with saturated aqueous solution No. ₁ HCO ₃ (10 ml) and extracted with 20% methanol / ESM ( 3x50 ml). The combined organic extracts were dried (Md8O _4), filtered, evaporated and chromatographed (0-20% methanol / OCM) to give the free base of the title compound as a solid light brown (20 mg, 32%).

M8 (E8 +) t / ζ 448 (MH ⁺ ).

Ή NMR (SPS1 ₃ , 400 MHz) δ 1.15-1.49 (2Н, m), 1.61-1.95 (2Н, m), 1.99-2.09 (2Н, m), 2 , 20-2.38 (1H, m), 2.45-2.85 (6H, m), 2.92-3.02 (1H, m), 3.05-3.15 (1H, m) 3.78 (2H, s), 4.20 (2H, t), 4.30-4.42 (1H, m), 4.52-4.61 (1H, m), 4.95-5 05 (1H, m), 6.23-6.32 (2H, m), 7.00 (1H, s), 7.47-7.50 (2H, m), 8.07 (1H, s )

The free base in the ESM was treated with 1 equiv. 1 M HC1 in diethyl ether and then evaporated to give the desired hydrochloride.

- 31 015821

Example 11. 7 - [({1 - [(4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridin-1-yl) methyl ] -4piperidinyl} amino) methyl] -2,3-dihydro-1,4-benzodioxin-5-carbonitrile hydrochloride (2: 1 mixture K: 8)

(a) 1,1-Dimethylethyl (1 - {(2K) -2-hydroxy-3- [7- (methyloxy) -2-oxo-3,4-dihydro-1,8-naphthyridine1 (2H) -yl] propyl} -4-piperidinyl) carbamate.

A mixture of 7- (methyloxy) -1 - [(2K) -2-oxiranylmethyl] -3,4-dihydro-1,8-naphthyridin-2 (1H) -one (prepared according to the general method of Example 5 (ί), but with using (2K) -2-oxiranylmethyl-3nitrobenzenesulfonate) (3.1 g, 13.3 mmol) and 1,1-dimethylethyl-4-piperidinylcarbamate (2.7 g, 13.3 mmol) in an IME (3 ml) at 110 ° C. for 1 h. IME was then evaporated. The crude product was purified by silica gel chromatography using a gradient of 0-10% methanol / dichloromethane to give the desired compound as a pale yellow solid, presumably enantiomer K (3.9 g; 89%; 90% purity).

M8 (E8 +) t / ζ 435 (MH ⁺ ).

(b) 1,1-Dimethylethyl {1 - [(4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridine- 2yl) methyl] -4-piperidinyl} carbamate (2: 1 mixture K: 8).

Solution 1,1-dimethylethyl (1 - {(2K) -2-hydroxy-3- [7- (methyloxy) -2-oxo-3,4-dihydro-1,8-naphthyridine1 (2H) -yl] propyl} -4-piperidinyl) carbamate (3.9 g, 8.97 mmol) in chloroform (150 ml) and triethylamine (3.1 ml) in an argon atmosphere was treated at ambient temperature with methanesulfonic acid anhydride (3.1 g, 17, 94 mmol) and then refluxed for 2.5 hours. The solvents were evaporated and the residue was dissolved in acetonitrile (150 ml) and treated with sodium iodide (6.7 g, 44.85 mmol) and heated at 80 ° C. After evaporation of acetonitrile for 45 min and separation of the residue between water (250 ml) and 20% methanol / dichloromethane (250 ml), the layers were separated and the aqueous layer was extracted with 20% methanol / dichloromethane (4x250 ml). The combined organic extracts were dried on magnesium sulfate, filtered and evaporated. The feed was purified by silica gel chromatography using a gradient of 0-10% methanol / dichloromethane to give the desired compound in the form of a bright orange foam (1.83 g; 57%, with triethylamine residues). The aqueous layer was evaporated and then chloroform was treated; the solid was filtered off and chloroform was evaporated, yielding 2.77 g of a yellow solid. The solid was dissolved in methanol and placed on an 8CX cartridge, previously wetted with methanol. The cartridge was washed with methanol (50 ml) and then 2 M ammonia in methanol (50 ml). 2 M ammonia in methanol was evaporated, yielding a pure product in the form of a white solid (220 mg), presumably a 2: 1 mixture of K: 8).

M8 (E8 +) t / ζ 403 (MH ⁺ ).

(c) 1,1-Dimethylethyl {1 - [(4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridin-1yl) methyl] -4-piperidinyl} carbamate (2: 1 mixture K: 8).

A mixture of 1,1-dimethylethyl {1 - [(4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridin2-yl) methyl] -4-piperidinyl} carbamate (2: 1 mixture K: 8) (1.83 g, 4.55 mmol) and ΌΌφ (1.6 g, 6.83 mmol) in

1,4-dioxane (100 ml) was stirred at 60 ° C. under argon overnight. An additional amount of ΌΌφ (1.6 g, 6.83 mmol) was added and the reaction mixture was stirred at 60 ° C for another 1 h. The reaction mixture was cooled to ambient temperature, treated with 5% aqueous potassium carbonate solution (600 ml) and extracted 20% methanol / dichloromethane (3x500 ml). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give the crude product in the form of a brown oil. L-M8 showed that there was still ~ 8% of the starting material, so the oil was combined with an additional amount of the starting material (220 mg) recovered from the aqueous solution in the previous step, and dissolved in 1,4-dioxane (100 ml), treated 1 eq. ΌΌφ and heated at 60 ° С for 1 h. LС-М8 showed that the reaction was not complete; therefore, 0.5 g of ΌΌφ was added and the reaction mixture was stirred at 60 ° С for 0.5 h. The study showed that the reaction was complete, therefore, the reaction mixture was treated with a 5% aqueous potassium carbonate solution (500 ml) and extracted with 20% methanol / dichloromethane (2x500 ml). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give the product in the form of a light brown foam (1 g, 50%).

M8 (E8 +) t / ζ 401 (MH ⁺ ).

(ά) 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9dion (2 : 1 mixture K: 8).

1,1-Dimethylethyl {1 - [(4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-c] - 1,8-naphthyridin-1-yl) methyl] 4 -piperidinyl} carbamate (2: 1 mixture K: 8) (1 g, 2.5 mmol) was dissolved in chloroform (10 ml) and treated with 4 M HC1 in a solution (10 ml) in 1,4-dioxane at ambient temperature . A solid precipitated, so some methanol was added to dissolve it. After 1 h, bCM8 showed that the reaction was complete, so additional methanol was added to dissolve

- 32 015821 create all the solid particles, after which toluene (~ 50 ml) was added. All solvents were evaporated under reduced pressure to give a yellow solid. The solid was dissolved in 100 ml of methanol and stirred with Llb2i81 A21 resin for 1 h. The resin was then filtered off and methanol was removed to give 0.7 g of a brown gum. The resin was dissolved in methanol and loaded onto an 8CX cartridge, which was previously wetted with methanol. The cartridge was washed with methanol and then 2 M ammonia in methanol. 2 M ammonia in methanol was evaporated, obtaining the product in the form of a light brown resin (0.6 g, 80%).

M8 (E8 +) t / ζ 301 (MH ⁺ ).

The product obtained by this general method was analyzed by chiral HPLC (Syngarak A8-H (5 μm) with 90: 10: 0.1 acetonitrile: methanol: isopropylamine as the mobile phase). The ratio of isomers (presumably E: 8) was approximately 2: 1.

(e) Target compound.

1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9-dione (2: 1 mixture K: 8) (60 mg, 0.2 mmol) and 7-formyl-2,3-dihydro-1,4-benzodioxin-5-carbonitrile (for synthesis, see XVO 06014580, production example 13 or XVO 2007122258 Example 31 (ά)) (37.8 mg, 0.2 mmol) was dissolved in dichloromethane / methanol (2/0, 1 ml) at ambient temperature under argon atmosphere and stirred at ambient temperature for 1 hour. Mixture then treated with No. 1BH (OAc) ₃ (85 mg, 0.4 mmol) and stirred for 1 h. Then, saturated sodium bicarbonate solution (15 ml) was added. and the aqueous layer was extracted with 20% methanol / dichloromethane (3x35 ml). The combined organic extracts were dried on magnesium sulfate, filtered and evaporated. The crude product was purified by silica gel chromatography using a gradient of 0-20% methanol / dichloromethane to give the free base of the title compound as a pale yellow gum (26 mg, 27%).

Ή NMR (SES1 ₃ , 250 MHz) δ 1.15-1.45 (m, 2H), 1.53 (s broad, 1H), 1.70-1.90 (m, 2H), 2.15 -2.35 (m, 1H), 2.35-2.55 (m, 1H), 2.55-2.75 (m, 2H), 2.85-3.00 (m, 2H), 3 , 00-3.15 (m, 1H), 3.68 (s, 2H), 4.25-4.45 (m, 5H), 4.50-4.65 (m, 1H), 4.90 -5.10 (m, 1H), 6.20-6.35 (m, 2H), 7.00-7.10 (m, 2H), 7.40-7.55 (m, 2H).

M8 (E8 +) t / ζ 474 (MH ⁺ ).

The target compound was obtained by dissolving the free base in an ESM and treating it with 1 equivalent. 1 M HC1 in diethyl ether. Then it was evaporated to dryness and dried in a vacuum desiccator in the presence of P ₂ O ₅ .

Example 12. 1 - [(4- {[(3-Oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2- dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride (2: 1 mixture K: 8)

about.

1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione (2: 1 mixture K: 8, for preparation see Example 11 (ά)) (60 mg, 0.2 mmol) and 3-oxo-3,4-dihydro-2H-

1,4-benzothiazine-6-carbaldehyde (for synthesis see XVO 2002056882, example 6 (c) (38.6 mg, 0.2 mmol) was dissolved in dichloromethane / methanol (2/0, 1 ml) at ambient temperature medium in an argon atmosphere and stirred at ambient temperature for 1 h. Then the mixture was treated with NaBN (OAc) s (85 mg, 0.4 mmol) and stirred for 1 h. Then saturated sodium bicarbonate solution (20 ml) was added and the aqueous layer was extracted with 20% methanol / dichloromethane (3x35 ml). The combined organic extracts were dried on magnesium sulfate, filtered and evaporated. Product was purified by chromatography on silica gel using a gradient of 0-20% methanol / dichloromethane to give the free base of the title compound as a yellow solid (37 mg, 39%).

Ή NMR (SES1 ₃ , 250 MHz) δ 1.20-1.45 (m, 2H), 1.70-2.15 (m, 4H), 2.15-2.40 (m, 2H), 2 40-2.75 (m, 3H),

2.95 (d, 1H), 3.05-3.15 (m, 1H), 3.40 (s, 2H), 3.76 (s, 2H), 4.30-4.45 (m, 1H), 4.50-4.65 (m, 1H), 4.90-5.10 (m, 1H), 6.20-6.35 (m, 2H), 6.85-7.00 ( m, 2H), 7.25 (d, 1H), 7.40-7.60 (m, 2H), 8.53 (s broad, 1H).

M8 (E8 +) t / ζ 478 (MH ⁺ ).

The target compound was prepared by dissolving the free base in ESM / MeOH and treating it with 1 equivalent. 1 M HC1 in diethyl ether. Then it was evaporated to dryness and dried in a vacuum desiccator in the presence of P2O5 for 4 days.

Example 13 A. (1K) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione hydrochloride (a) 6- (methyloxy) -3-nitro-2-pyridinamine.

- 33 015821

A solution / suspension of 2-chloro-6- (methyloxy) -3-nitropyridine (65.7 g, 348 mmol) in 2 M ammonia in methanol (500 ml, 1000 mmol) and aqueous ammonia (500 ml, 348 mmol) was stirred at 65 ° C for 18 hours. The reaction mixture was cooled and the solid was filtered and washed with water (2x100 ml). The solid was dried in a vacuum oven at 40 ° C. overnight to give the product in the form of a bright yellow solid (52.14 g, 84% NMR purity, 74%).

M8 (E8 +) t / ζ 170 (MH ⁺ ).

(b) 6- (methyloxy) -2,3-pyridinediamine.

6- (Methyloxy) -3-nitro-2-pyridinamine (26 g, 129 mmol) was suspended in ethanol (500 ml) at ambient temperature under argon atmosphere and then treated with palladium on carbon (15 g, 14.10 mmol) ( 10% paste). The reaction mixture was stirred at less than 1 atm. hydrogen overnight. The reaction mixture was filtered through a pad of celite and this pad was washed with ethanol (500 ml). Ethanol was evaporated to give the product in the form of a violet oil (20.68 g, crude).

M8 (E8 +) t / ζ 140 (MH ⁺ ).

(c) N- [2 - amino-6- (methyloxy) -3-pyridinyl] ethyl glycinate.

6- (Methyloxy) -2,3-pyridinediamine (21.7 g, approximately 87% purity, 136 mmol) was dissolved in acetonitrile (500 ml) at ambient temperature under argon atmosphere and then treated with potassium carbonate (24.38 g, 176 mmol) and ethyl bromoacetate (18.13 ml, 163 mmol). The reaction mixture was stirred at ambient temperature overnight. Acetonitrile was then removed in vacuo. The reaction was repeated using additional 6- (methyloxy) -2,3-pyridinediamine (20.68 g, 87% pure, 129 mmol) in acetonitrile (500 ml), potassium carbonate (23.23 g) and ethyl bromoacetate (17.27 g), the reaction mixture was again stirred at ambient temperature overnight, and acetonitrile was then removed in vacuo. The residues were partitioned between water (1 L) and ethyl acetate (1 L) and the layers were separated. The aqueous layer was extracted once more with ethyl acetate (1 L) and the combined organic extracts were dried over MgSO4, filtered and evaporated to give a purple oil (64 g). The oil was treated with an ESM (300 ml) and insoluble impurities were filtered off. The ESM solution was loaded onto a 800 g silica gel column and eluted with 0-2% MeOH / OSM to obtain 40.6 g of the desired product in the form of a brown solid (LCM8 and NMR correspond to 75% of the desired product with 15% cyclized product 6- (methyloxy ) -1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one and 6.4 g of the cyclized product 6- (methyloxy) -1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one in the form of a violet solid.

M8 (E8 +) t / ζ 226 (MH ⁺ ).

(ά) 6- (methyloxy) -1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one.

No. [2-amino-6- (methyloxy) -3-pyridinyl] ethyl glycinate (40.6 g, 135 mmol) was dissolved in tetrahydrofuran (THE) (1 L) at ambient temperature under argon atmosphere and treated with potassium t-butoxide (15, 17 g, 135 mmol). After 2 hours at ambient temperature, a saturated solution of ΝΉ ₄ Ο (500 ml) was added, and ТНЕ were evaporated. Water (500 ml) was added, followed by 20% MeOH / OCM (1 L); insoluble material was filtered off, washed with diethyl ether and dried in a vacuum oven at 40 ° С overnight to obtain the desired product in the form of a yellow solid (15.3 g): LСМ8 and NMR corresponded to the product (9% oxidized material according to NMR).

These two phases were transferred to a separatory funnel and separated. The aqueous layer was extracted twice more with 20% MeOH / OCM (2x500 ml) and the combined organic extracts were dried over MD8O4, filtered and evaporated to give a brown solid, which was washed with additional diethyl ether to give an additional amount of the desired product in the form of a solid light green substances (7.7 g): LСМ8 and NMR corresponding to the product (20% of the oxidized material according to NMR data).

M8 (E8 +) t / ζ 180 (MH ⁺ ).

Alternative procedure.

No. [2-Amino-6- (methyloxy) -3-pyridinyl] ethyl glycinate (16.2 g, 72 mmol) was dissolved in tetrahydrofuran (500 ml) and cooled to 0 ° C (cooling in an ice bath) under argon atmosphere. Then the solution was treated with potassium tert-butoxide (1 M in THE, 80 ml, 80 mmol). After 1.5 hours, the reaction mixture was treated with acetic acid (80 mmol) and evaporated to give a dark solid. This solid was triturated with water (200 ml), filtered and dried in vacuo (~ 13 g, quant.), After which it can be used without further purification.

(f) 6- (methyloxy) -3-oxo-3,4-dihydropyrido [2,3-b] pyrazin-1 (2H) phenylmethylcarboxylate.

To 6- (methyloxy) -1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one (6.35 g, 35.4 mmol) in ethyl acetate (600 ml) / sodium bicarbonate (sat. solution) (200 ml) with vigorous stirring, benzyl chloroformate (5.31 ml, 37.2 mmol) was added at ambient temperature. After 45 minutes, the reaction was complete. The layers were separated and the organic layer was dried on magnesium sulfate, filtered and evaporated to give the desired product as an off-white solid (11 g, 99%).

- 34 015821

M8 (E8 +) t / ζ 314 (MH ⁺ ).

(ί) 6- (methyloxy) -4 - [(2K) -2-oxiranylmethyl] -3-oxo-3,4-dihydropyrido [2,3-b] pyrazin-1 (2H) phenylmethylcarboxylate.

6- (Methoxy) -3-oxo-3,4-dihydropyrido [2,3-b] pyrazin-1 (2H) -phenylmethylcarboxylate (11 g, 35.1 mmol) was dissolved in OME (300 ml) at ambient temperature in an argon atmosphere, getting a yellow solution. The solution was then cooled in an ice bath and treated with sodium hydride (1.685 g, 42.1 mmol). The solution was allowed to warm to ambient temperature. After 20 minutes, (28) -2-oxiranylmethyl-3-nitrobenzenesulfonate (9.56 g, 36.9 mmol) was added. After 1 h, all the starting material was consumed; therefore, the reaction mixture was treated with saturated sodium bicarbonate solution (350 ml) and the aqueous layer was extracted with ESM (3x400 ml). The combined organic layers were dried on magnesium sulfate, filtered and evaporated to give a light brown oil (16.93 g). The product was used as the crude product in the next step.

M8 (E8 +) t / ζ 370 (MH ⁺ ).

(e) (18) -1- (Hydroxymethyl) -3,8-dioxo-1,2,3,4-tetrahydro-5H, 8H-2a, 5,8a-triazacenaphthylene-5phenylmethylcarboxylate.

6- (Methyloxy) -4 - [(2K) -2-oxiranylmethyl] -3-oxo-3,4-dihydropyrido [2,3-b] pyrazin-1 (2H) phenylmethylcarboxylate (crude product, 15.93 g, presumably 32.8 mmol) was dissolved in OME (250 ml) at ambient temperature and heated at 130 ° C for 2 nights and at 120 ° C for 1 night. The reaction was complete, so the OME was evaporated and the residue was treated with water / brine (350/50 ml) and an ESM (500 ml). The layers were separated and the aqueous layer was extracted once more with ESM (500 ml). The combined organic extracts were dried on magnesium sulfate, filtered and evaporated to give a brown oil, which was dried under high vacuum over the weekend. The crude product was purified by silica gel chromatography using a 0-10% methanol / dichloromethane gradient to give the desired product in the form of a golden foam (3.6 g, 30.9%).

M8 (E8 +) t / ζ 356 (MH ⁺ ).

(I) (18) -1- (Hydroxymethyl) -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione. (18) -1- (Hydroxymethyl) -3,8-dioxo-1,2,3,4-tetrahydro-5H, 8H-2a, 5,8a-triazacenaphthylene-5 phenylmethyl carboxylate (1.6 g, 4.50 mmol) dissolved in ethanol (100 ml) at ambient temperature and then treated with palladium on charcoal (10% paste) (1 g, 0.940 mmol). The mixture was stirred at ambient temperature at less than 1 atm. hydrogen for 3 hours. The reaction mixture was then filtered through a pad of celite and the impurities were washed with additional ethanol. The product was then eluted with OME (400 ml) and the OME was evaporated to give a brown solid (780 mg). This solid was then suspended in 30% HeΟH / ^ CΜ (150 ml) and stirred with manganese dioxide (1.174 g, 13.51 mmol) at ambient temperature for 5 hours and then filtered through a pad of celite, which was washed with 20% methanol / dichloromethane (100 ml). The solvents were evaporated to give the desired compound as a brown solid (750 mg, 76%).

M8 (E8 +) t / ζ 220 (MH ⁺ ).

(ί) [(18) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-1-yl] methyl methanesulfonate.

(18) -1- (Hydroxymethyl) -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione (750 mg,

3.42 mmol) was suspended in a dry ESM (100 ml) at ambient temperature under argon and then treated with triethylamine (0.572 ml, 4.11 mmol). The mixture was then cooled using an ice water bath. Then methanesulfonyl chloride (0.293 ml, 3.76 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 50 minutes, no starting material remained, so the mixture was washed with a saturated solution of Να4ΠΟ ₃ (100 ml). The aqueous layer was extracted with 20% HeΟH / ^ CΜ (2x100 ml); the combined organic extracts were dried on magnesium sulfate, filtered and evaporated, obtaining the product in the form of a brown foam (1.05 g, 90% purity according to LMS8).

M8 (E8 +) t / ζ 297.9 (MH ⁺ ).

(ί) 1,1-Dimethylethyl (1 - {[((1K) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-1yl] methyl} -4-piperidinyl) carbamate.

A solution of [(18) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-1-yl] methyl methanesulfonate (1.05 g, 3.53 mmol) in dry acetonitrile ( 50 ml) at ambient temperature under argon, was treated with pyridine (0.343 ml, 4.24 mmol), then 1,1-dimethylethyl 4-piperidinyl carbamate (0.884 g, 4.24 mmol). The mixture was heated at 70 ° C for 1.5 hours and then at 90 ° C for 3 hours. Lc-M8 showed ~ 25% of the product. 0.5 equiv. pyridine and 0.5 equiv.

1,1-dimethylethyl-4-piperidinyl carbamate and the reaction mixture were heated at 90 ° C. overnight and then stirred at ambient temperature for 2 days. The reaction was complete. The solvent was evaporated and the residue was partitioned between sat. NaHCΟ ₃ and 20% methanol / dichloromethane (100 ml / 100 ml). The layers were separated and the aqueous layer was again extracted with 20% methanol / dichloromethane (2x100 ml). The combined organic extracts were dried on magnesium sulfate, filtered and evaporated to give 1.7 g of a crude product, which was purified by silica gel chromatography using

- 35 015821 gradient 0-5% methanol / dichloromethane, obtaining the product in the form of a yellow solid (0.57 g, 40.2%).

M8 (E8 +) t / ζ 402 (MH ⁺ ).

(k) (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8dione dihydrochloride.

Solution 1,1-dimethylethyl (1- {[(1K) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-1 yl] methyl} -4-piperidinyl) carbamate (0.57 g, 1.420 mmol) in chloroform (7 ml) at ambient temperature was treated with 4 M HC1 in 1,4-dioxane (7 ml). The solid precipitated and the mixture was stirred at ambient temperature. After 0.5 h, some methanol was added to dissolve most of the solid, after which toluene was added and all solvents were removed to give the product as a yellow solid (0.53 g, 100%).

M8 (E8 +) t / ζ 302 (MH ⁺ ).

(l) Target compound.

Suspension (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione dihydrochloride (165 mg, 0.441 mmol) in chloroform (10 ml) and methanol (0.4 ml) were treated with triethylamine (0.184 ml, 1.333 mmol) at ambient temperature under argon atmosphere and stirred for 0.25 h (suspension turned into a solution). Then, [1,3] oxathiolo [5,4s] pyridine-6-carbaldehyde was added (for synthesis see \ UO 2004058144, example 61) (73.7 mg, 0.441 mmol) and the reaction mixture was stirred at ambient temperature for 0.5 h. Sodium triacetoxyborohydride (280 mg, 1.323 mmol) was then added and the reaction mixture was stirred at ambient temperature. After 1.5 h, L-M8 showed that there was still some imine remaining in the mixture, so 1 equiv. sodium triacetoxyborohydride. After 1 h, a saturated NaHCO3 solution (50 ml) was added, then 20% methanol / dichloromethane (80 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted twice with 20% methanol / dichloromethane (2x80 ml). The combined organic extracts were dried on magnesium sulfate, filtered and evaporated to give 215 mg of a crude product, which was purified by silica gel chromatography using a 0-20% methanol / dichloromethane gradient to give the yellow base of the title compound as a yellow solid (185 mg, 93 %).

Ή NMR (СОС1 ₃ , 250 MHz) δ 1.20-1.45 (m, 2Н), 1.75-2.75 (m, 8Н), 2.94 (d, 1Н), 3.00-3 15 (m, 1H), 3.81 (s, 2H), 4.30-4.45 (m, 1H), 4.50-4.65 (m, 1H), 4.90-5.10 (m, 1H), 5.74 (s, 2H), 6.34 (d, 1H), 7.19 (s, 1H), 7.77 (d, 1H), 7.87 (s, 1H) 7.99 (s, 1H).

M8 (E8 +) t / ζ 453 (MH ⁺ ).

The target compound was obtained by dissolving the free base in methanol / dichloromethane and treating it with 1 equiv. 1 M HC1 in diethyl ether. Then it was evaporated to dryness and dried in a vacuum desiccator in the presence of P2O5.

Example 13B (1B) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione benzoate.

(1B) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a , 5,8a-triazacenaphthylene-3,8-dione hydrochloride (45 mg, 0.092 mmol) was purified using an ΆΌ-H column with CH ₃ CH: CH ₃ OH: 1% isopropylamine. The main peak was collected and the solvent was removed. Benzoate was prepared by dissolving the compound in MeOH and adding 1 equiv. benzoic acid. The solution was stirred for 1 h, the solvent was removed to give the product.

Example 13C (1B) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione fumarate.

(1B) -1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a , 5,8a-triazacenaphthylene-3,8-dione hydrochloride (49 mg, 0.100 mmol) was dissolved in 10 ml of MeOH and 2 g (pre-moistened with methanol) were loaded onto an 8CX cartridge. The crude product was adsorbed onto the cartridge and then the cartridge was washed with methanol (15 ml). The product was eluted using 2 M ΝΉ ₃ in methanol (15 ml); the fraction containing the product was evaporated to give the product which is a free amine (41.5 mg, 92% reduction). BCM8 and NMR, corresponding to the product. Free amine was dissolved in a small amount of ESM / Meon. treated with 1 equiv. fumaric acid (10.6 mg) and stirred for 10 minutes The solvents were removed and the solid was dried in an desiccator (P ₂ O ₅ ) overnight to give the product in the form of a white solid (51 mg, LCM8 and NMR corresponding to the product).

- 36 015821

Example 14. (1B) -1 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1piperidinyl} methyl) -1.2 -dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Suspension (1 B) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione dihydrochloride (160 mg, 0.428 mmol) (for preparation see example 13 (k) or 15 (ά)) in chloroform (10 ml) and methanol (0.400 ml) in an argon atmosphere at ambient temperature triethylamine (0.179 ml, 1.283 mmol) and stirred for 0.25 hours at ambient temperature (the mixture turned into a solution). Then 2,3-dihydro [1,4] oxathiino [2,3s] pyridin-7-carbaldehyde was added (for synthesis see \ UO 2004058144, example 60) (77 mg, 0.428 mmol) and the reaction mixture was stirred at ambient temperature medium for 0.5 hours. Sodium triacetoxyborohydride (272 mg, 1.283 mmol) was then added and the reaction mixture was stirred at ambient temperature. After 1.5 hours, there was still some imine (L-M8), so 1 equiv. sodium triacetoxyborohydride. After 1 h, sat. NaHCO ₃ (50 ml), then 20% methanol / dichloromethane (80 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted twice with 20% methanol / dichloromethane (2x80 ml). The combined organic extracts were dried on Md8O _4, filtered and evaporated to give 215 mg of crude product which was purified by chromatography on silica gel using a gradient of 0-20% methanol / dichloromethane to give the free base of the title compound as a yellow foam (179 mg, 90%) .

Ή NMR (SPS1 ₃ , 250 MHz) δ 1.20-1.50 (m, 2H), 1.85 (t, 2H), 1.95-2.40 (m, 3H), 2.45-2 75 (m, 3H), 2.94 (d, 1H), 3.05-3.20 (m, 3H), 3.69 (s, 2H), 4.30-4.50 (m, 3H) ), 4.50-4.65 (m, 1H), 4.90-5.10 (m, 1H), 6.33, (d, 1H), 6.99 (s, 1H), 7.67 (d, 1H), 7.86 (s, 1H), 8.01 (s, 1H).

M8 (E8 +) w / ζ 467 (MH ⁺ ).

The target compound was prepared by dissolving the free base in ESM / MeOH and treating it with 1 equivalent. 1 M HC1 in diethyl ether. Then it was evaporated to dryness and dried in a vacuum desiccator in the presence of P2O5.

Example 15. (1B) -1 - ({4 - [(2,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1 piperidinyl} methyl) -1.2 -dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione dihydrochloride

(a) (18) -1 - {[(Methylsulfonyl) oxy] methyl} -3,8-dioxo-1,2,3,4-tetrahydro-5H, 8H-2a, 5,8-triazacenaphthylene-5-phenylmethylcarboxylate.

(18) -1- (Hydroxymethyl) -3,8-dioxo-1,2,3,4-tetrahydro-5H, 8H-2a, 5,8a-triazacenaphthylene-5 phenylmethyl carboxylate (242 mg, 0.681 mmol) (in relation to the preparation see example 13 (d)) was dissolved in an ESM (10 ml) at ambient temperature under argon and then treated with triethylamine (0.114 ml, 0.817 mmol). The mixture was then cooled using an ice water bath. Then methanesulfonyl chloride (0.058 ml, 0.749 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the mixture was washed with sat. NaHCO ₃ (10 ml). The aqueous layer was extracted with SEM (2x50 mL) and the combined organic extracts were dried on Md8O _4, filtered and evaporated to give the product as a yellow foam (232 mg, 95% purity LC-M8, 74.7%).

M8 (E8 +) w / ζ 434 (MH ⁺ ).

(b) (1 B) -1 - {[4 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -1-piperidinyl] methyl} -3,8-dioxo

1,2,3,4-tetrahydro-5H, 8H-2a, 5,8a-triazacenaphthylene-5-phenylmethylcarboxylate.

(18) -1 - {[(Methylsulfonyl) oxy] methyl} -3,8-dioxo-1,2,3,4-tetrahydro-5H, 8H-2a, 5,8-triazacenaphthylene-5-phenylmethylcarboxylate (232 mg, 0.508 mmol) was dissolved in dry acetonitrile (10 ml) at ambient temperature under argon and treated with pyridine (0.049 ml, 0.610 mmol). Then 1,1-dimethylethyl-4-piperidinyl carbamate (127 mg, 0.610 mmol) was added and the reaction mixture was heated at 70 ° C. overnight. Then, 0.049 ml of pyridine and 127 mg of 1,1-dimethylethyl-4-piperidinyl carbamate were added to the reaction mixture, the temperature was increased to 80 ° C. over 8 hours, and then the reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated and the residue was partitioned between sat. NaHCO ₃ and ESM (.50 / 50 ml). The layers were separated and the aqueous layer was again extracted with ESM (2x50 ml). The combined organic extracts were dried (MD8O4), filtered and evaporated to give 280 mg of a crude product, which was purified by silica gel chromatography using a 0-5% methanol / dichloromethane gradient to give a yellow gum product (130 mg, 47.6%).

M8 (E8 +) w / ζ 538 (MH ⁺ ).

37 015821 (c) 1,1-Dimethylethyl (1 - {[((1H) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-1yl] methyl} -4 -piperidinyl) carbamate.

(1H) -1 - {[4 - ({[(1,1-Dimethylethyl) oxy] carbonyl} amino) -1-piperidinyl] methyl} -3,8-dioxo-1,2,3,4tetrahydro-5H, 8H-2a, 5,8a-triazacenaphthylene-5-phenylmethylcarboxylate (130 mg, 0.242 mmol) was dissolved in ethanol (10 ml) at ambient temperature and then treated with palladium on charcoal (10% paste) (100 mg, 0.094 mmol). The solution was stirred at ambient temperature at less than 1 atm. hydrogen for 3 hours. The reaction mixture was then filtered through a pad of celite and washed with additional ethanol (50 ml). Ethanol was evaporated to give a yellow gum (79 mg), which was dissolved in an ESM (~ 10 ml) and stirred with manganese dioxide (63.1 mg, 0.725 mmol) at ambient temperature overnight. Then another 1.5 eq. manganese dioxide (32 mg) and the reaction mixture was stirred at ambient temperature for 3 hours. Lc-M8 showed the presence of starting material, so 2 equiv. manganese dioxide. The reaction mixture was stirred at ambient temperature for 2 hours, then filtered through a pad of celite. The celite layer was washed with an ESM and the solvents evaporated to give the product in the form of a brown solid (76 mg, 78%).

M8 (E8 +) t / ζ 402 (MH ⁺ ).

(ά) (1H) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3.8 dione dihydrochloride.

Solution 1,1-dimethylethyl (1- {[(1H) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-1 yl] methyl} -4-piperidinyl) carbamate (76 mg, 0.189 mmol) in chloroform (2 ml) at ambient temperature was treated with 4 M HC1 in 1,4-dioxane (2 ml). A solid precipitated and the mixture was stirred at ambient temperature. After 0.5 h, the reaction was complete, so some methanol was added to dissolve most of the solid, after which toluene was added and all solvents were removed to give the product as a dark yellow solid (70.9 mg, 99%) .

M8 (E8 +) t / ζ 302 (MH ⁺ ).

(e) Target compound.

Suspension (1K.) - 1 - [(4-amino-1-piperidinyl) methyl] - 1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione dihydrochloride (70 mg, 0.187 mmol) in chloroform (5 ml) and methanol (0.2 ml) were treated with triethylamine (0.078 ml, 0.561 mmol) at ambient temperature under argon atmosphere and stirred for 0.25 h. The mixture turned into a solution; then added

2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-carbaldehyde (for synthesis see VO 2004058144, example 2 (c) or VO 03/087098, example 19 (ά))) (30.9 mg, 0.187 mmol) and the reaction mixture was stirred at ambient temperature for 0.5 hours. Sodium triacetoxyborohydride (119 mg, 0.561 mmol) was then added and the reaction mixture was stirred at ambient temperature. After 1.5 hours, another 1 eq. sodium triacetoxyborohydride. After 1 h, sat. NaHCO ₃ (50 ml), then 20% MeOH / OCM (50 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted twice with 20% MeOH / ESM (2x50 ml). The combined organic extracts were dried on Md8O _4, filtered and evaporated to give 90 mg of crude product which was purified by chromatography on silica gel using a gradient of 0-20% methanol / dichloromethane to give the free base of the title compound as a pale yellow gum (60 mg, 71 %).

Ή NMR (SES1 ₃ , 250 MHz) δ 1.25-1.50 (m, 2H), 1.86 (t, 2H), 2.10-2.75 (m, 6H), 2.93 (d , 1H), 3.00-3.15 (m, 1H), 3.79 (s, 2H), 4.20-4.45 (m, 5H), 4.50-4.65 (m, 1H ), 4.90-5.10 (m, 1H), 6.33 (d, 1H), 6.82 (s, 1H), 7.76 (d, 1H), 7.86 (s, 1H) 8.11 (s, 1H).

M8 (E8 +) t / ζ 451 (MH ⁺ ).

The target compound was prepared by dissolving the free base in ESM / MeOH and treating it with 2 eq. 1 M HC1 in diethyl ether. Then it was evaporated to dryness and dried in a vacuum desiccator in the presence of P2O5.

Example 16A (2H) -2 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

(a) 2 - {[6- (Methyloxy) -3-nitro-2-pyridinyl] amino} -1,3-propanediol.

6-Methoxy-2-chloro-3-nitropyridine (36.94 g, 195.9 mmol) and 2-aminopropane-1,3-diol (35.65 g,

391.3 mmol, 2 equiv.) Was stirred in ethanol (500 ml) under reflux in argon atmosphere for 3 hours. The mixture was allowed to cool to ambient temperature and left overnight. The solvent was partially removed under reduced pressure (to about 150 ml) and the resulting

- 38 015821 a bright yellow liquid solution was poured into ice water (1.5 L) with vigorous stirring. The mixture was stirred for 1 h, then filtered by suction while cooling. This solid was washed with ice-cold water (200 ml) and dried in air to give the title compound as a bright yellow solid (45.03 g, 94%). LS-M8 showed the desired product (93%) plus 7% of the starting material. The product was used without further purification.

M8 (E8 +) t / ζ 244 (MH ⁺ ).

(b) No. (2,2-Dimethyl-1,3-dioxan-5-yl) -6- (methyloxy) -3-nitro-2-pyridinamine.

2 - {[6- (Methyloxy) -3-nitro-2-pyridinyl] amino} -1,3-propanediol (53.93 g, 228.7 mmol) was stirred in 2,2-dimethoxypropane (900 ml) in the atmosphere argon and p-toluenesulfonic acid monohydrate (1.00 g) was added. The mixture was stirred at ambient temperature overnight. It was diluted with dichloromethane (1 L) and the resulting solution was treated with saturated aqueous sodium bicarbonate (20 ml) and solid sodium bicarbonate (20 g) with vigorous stirring (boiling). The mixture was vigorously stirred for 20 minutes, then the remaining water was absorbed by the addition of anhydrous sodium sulfate. The mixture was filtered by suction and the solids were washed with an ESM (500 ml). The combined filtrate plus washings were evaporated under reduced pressure to give a yellow solid, which was stirred with petroleum ether (40-60 °) over the weekend. The solid was isolated by suction filtration, washed with petroleum ether (40-60 ° C) and dried in air to give the title compound as a bright yellow solid in the form of 57.83 g, 92%).

M8 (E8 +) t / ζ 284 (MH ⁺ ).

(c) Ν ² - (2,2-Dimethyl-1,3-dioxan-5-yl) -6- (methyloxy) -2,3-pyridinediamine.

No. (2,2-Dimethyl-1,3-dioxan-5-yl) -6- (methoxy) -3-nitro-2-pyridinamine (35.00 g, 123.6 mmol) was divided into 2 aliquots, each which were suspended in 1,4-dioxane (500 ml) and hydrogenated at 10% Ρά on carbon (paste, 1: 1 wt.: wt. with water, 4.00 g) under a pressure of 1 atm hydrogen, at ambient temperature overnight. The mixture was filtered with suction through celite, using a protective atmosphere of argon and trying to minimize contact of the product with air. The solution was evaporated under reduced pressure to obtain the desired compound in the form of a saturated violet oil. It was used immediately in the next stage.

M8 (E8 +) t / ζ 254 (MH ⁺ ).

(ά) No. [2 - [(2,2-Dimethyl-1,3-dioxan-5-yl) amino] -6- (methyloxy) -3-pyridinyl] ethyl glycinate.

The crude 4- (2,2-dimethyl-1,3-dioxan-5-yl) -6- (methoxy) -2,3-pyridinediamine obtained in Example 16A (c) (presumably 123.6 mmol) was dissolved in anhydrous EMU (500 ml) in an argon atmosphere and anhydrous potassium carbonate (37.56 g, 2.2 eq.) Was added, followed by ethyl bromoacetate (12.31 ml, 0.9 eq.). The mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, and the resulting reddish-brown liquid solution was partitioned between an ESM (1.2 L) and water (300 ml). The organic phase was separated and washed with water (300 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a dark red oil, which was suspended in a minimum of ESM and purified by silica gel column chromatography (eluting with 5-60% ethyl acetate in petroleum ether (40-60 °)). The appropriate fractions were combined and evaporated under reduced pressure to obtain the target compound in the form of a dark orange oil (35.42 g, 84%).

M8 (E8 +) t / ζ 340 (MH ⁺ ).

(e) 4- (2,2-Dimethyl-1,3-dioxan-5-yl) -6- (methyloxy) -1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one.

No. [2 - [(2,2-Dimethyl-1,3-dioxan-5-yl) amino] -6- (methyloxy) -3-pyridinyl] ethyl glycinate (35.42 g,

104.4 mmol) was dissolved in dry ТНЕ (500 ml) and the solution was added dropwise over 2 h to a cooled (0 ° С) suspension of sodium hydride (4.173 g of 60% wt.: Weight dispersion in oil, 1.00 eq. ) in dry THE (500 ml) in an argon atmosphere. During the addition, the color of the suspension changed from orange to green. The mixture was stirred at 0 ° C for another 15 minutes, then it was allowed to warm to ambient temperature and stirred at ambient temperature for 1 h. The mixture was cooled to 0 ° C and a saturated solution of ammonium chloride (15 ml) was carefully added with vigorous stirring (observed boiling). After the boiling stopped, the mixture was allowed to warm to ambient temperature and was stirred for 4 hours, then diluted with ethyl acetate (500 ml) and filtered with suction. The solids were washed with ethyl acetate (300 ml) and the combined filtrate plus washings were evaporated under reduced pressure to give a dark brown solid. It was stirred with petroleum ether (40-60 °) (500 ml) plus ethyl acetate (20 ml) for 2 hours and filtered with suction to give a lighter brown solid that was washed with petroleum ether (40-60 °) ( 100 ml) and dried in air, obtaining the target compound in the form of an amorphous yellow-brown solid (25.37 g, 82.8%).

M8 (E8 +) t / ζ 316 (M№ ⁺ ).

(ί) 4- (2,2-Dimethyl-1,3-dioxan-5-yl) -6- (methyloxy) pyrido [2,3-b] pyrazin-3 (4H) -one.

4- (2,2-Dimethyl-1,3-dioxan-5-yl) -6- (methyloxy) -1,4-dihydropyrido [2,3-b] pyrazin-3 (2H) -one (25.37 d) and activated manganese dioxide (120 g, ~ 15 equiv.) were stirred in an ESM (500 ml) at ambient temperature for 2 hours, then overnight. The mixture was filtered by suction and

- 39 015821 solids were washed with ΩΟΜ (2x100 ml). The combined filtrate plus washings were evaporated under reduced pressure to give a brown foam; it was purified by silica gel column chromatography (eluting with 0-100% ethyl acetate in petroleum ether (40-60 °)). The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a pale yellow brown solid (17.40 g, 69%).

Μ8 (E8 +) t / ζ 314 (ΜΝ1 ').

(e) 4- [2-G idroxy-1 - (hydroxymethyl) ethyl] -6- (methyloxy) pyrido [2,3-L] pyrazin-3 (4H) -one.

4- (2,2-Dimethyl-1,3-dioxan-5-yl) -6- (methyloxy) pyrido [2,3-b] pyrazin-3 (4H) -one (17.40 g,

59.7 mmol) was dissolved in tetrahydrofuran (THE) (220 ml) to give a dark yellow solution. A 1 M aqueous solution of HC1 (200 ml) was added (transitional blues and greens appeared in the solution) and the light yellow solution was stirred at ambient temperature for 1 h. The mixture was concentrated to approximately 300 ml on a rotary evaporator using a cold water bath (some solid precipitated during this procedure), then vigorously stirred, adding solid sodium bicarbonate in portions (caution: boiling) until the mixture reaches a pH of approximately 8. The resulting yellow solid is irali filtration with suction, washed with water (2x20 ml) and air dried to give the title compound as an amorphous yellow solid (13.805 g, 91%).

Μ8 (E8 +) t / ζ 252 (MH ⁺ ).

(1) (3,8-dioxo-1,2,5a, 8b-tetrahydro-3H, 8H-2a, 5,8a-triazacenaphthylene-2-yl) methyl methanesulfonate.

4- [2-hydroxy-1- (hydroxymethyl) ethyl] -6 (methoxy) pyrido [2,3-b] pyrazin-3 (4H) -one (11.330 g, 45.1 mmol) was placed in a 1 L round bottom flask ) Anhydrous chloroform (280 ml) was added, followed by triethylamine (31.4 ml, 225 mmol) and methanesulfonic anhydride (31.4 g, 180 mmol) to obtain a dark yellow-brown solution. During the addition of methanesulfonic acid anhydride, an exothermic effect was observed which was sufficient to boil the solvent. The mixture was vigorously stirred under reflux in argon atmosphere for 4.5 hours. The mixture was allowed to cool to ambient temperature, diluted with ΩΕΜ to approximately 600 ml and washed with water (200 ml). The organic phase was separated and the aqueous phase was extracted with ΩΟΜ (2x200 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude mesylate in the form of a dark brown oil. It was left overnight at 40-60 ° petroleum ether (200 ml) plus ΩΟΜ (50 ml). The obtained solid substance was isolated by suction filtration, washed with 4: 1 petroleum ether: ^ СΜ (2x50 ml) and dried in air, obtaining the target compound in the form of an amorphous brown solid (6.950 g, 52%).

Μ8 (E8 +) t / ζ 332 (ΜΝ1 '). 298 (MH ⁺ ).

(ί) 1,1 - Dimethylethyl {1 - [(3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-2-yl) methyl] -4 piperidinyl} carbamate.

The crude product (3,8-dioxo-1,2,5a, 8L-tetrahydro-3H, 8H-2a, 5,8a-triazacenaphthylene-2-yl) methyl methanesulfonate (6.950 g, 23.38 mmol) was dissolved in dry acetonitrile (200 ml) and the mixture was treated with pyridine (7.55 ml, 94.0 mmol), then 1,1-dimethylethyl-4-piperidinyl carbamate (10.30 g,

51.4 mmol). The mixture was stirred under reflux under argon for 3 hours, then at 50 ° C. over the weekend. The mixture was then stirred at 90 ° C for 2 hours, then the volatiles were removed under reduced pressure and the residue was partitioned between ϋί, Μ (600 ml) and water (100 ml). The organic phase was separated and the aqueous phase was extracted with ΩΟΜ (2x200 ml). The combined organic extracts were washed with water (2x100 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a dark yellow brown solid; it was suspended in a minimum of 5% MeOH in ΩΕΜ and chromatographed on silica gel, eluting with 0-10% MeOH in ΩΟΜ. The appropriate fractions were combined and evaporated under reduced pressure to obtain the desired compound in the form of a pale yellow-brown amorphous solid (5.444 g, 56.8 ° C.).

Μ8 (E8 +) t / ζ 424 (ΜΝ1 '). 402 (MH ⁺ ).

(ί) 2 - [(4-amino-1-piperidinyl) methyl] - 1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione (racemic synthesis and synthesis of enantiomers 1 and 2 )

Method A (racemic synthesis).

1,1-Dimethylethyl {1 - [(3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-2-yl) methyl] -4 piperidinyl} carbamate (1,630 g, 4, 06 mmol) was suspended in ΩΟΜ (30 ml) and 4 M HC1 was added to

1,4-dioxane (15 ml) to give a bright yellow suspension (and gas evolution). The bright yellow mixture was left to stand at ambient temperature for 1 h. ^ Ç did not show the preservation of the starting material. The solvents were removed under reduced pressure, and the residue was dried under reduced pressure overnight to obtain the dihydrochloride of the target compound in the form of a tan amorphous solid (1.760 g (> theoretical yield for dihydrochloride due to the presence of a residual solvent).

- 40 015821

A portion of the crude dihydrochloride (0.513 g) was dissolved in methanol (4 ml) plus water (1 ml) and transferred to an 8CX column (10 g) (preconditioned with 2 volumes of a methanol column). The column was then eluted. under gravity. using (1) methanol (2x50 ml). (ίί) 0.5 M ammonia in methanol (fractions of 3x50 ml). The appropriate fractions were combined and evaporated under reduced pressure. obtaining the crude target compound in the form of an amorphous yellow-brown solid (410 mg). which contained methanol-insoluble material. which was not detected by bCM8 (possibly ammonium chloride). The product was shaken with methanol (30 ml) and the suspension was filtered. The solid was washed with methanol (20 ml) and the combined filtrate and washings were evaporated under reduced pressure. receiving the target compound (360 mg. 87%).

M8 (E8 +) t / ζ 302 (MH ⁺ ).

Method B.

1.1-Dimethylethyl {1 - [(3.8-dioxo-1.2-dihydro-3H.8H-2a.5.8a-triazacenaphthylene-2-yl) methyl] -4 piperidinyl} carbamate (9.735 g. 24.25 mmol) was suspended in an ESM (90 ml ) and 4 M HC1 was added to

1.4-dioxane (45 ml). getting a bright yellow suspension (and gas evolution). The bright yellow mixture was stirred at ambient temperature for 1 hour. Solvents were removed under reduced pressure. obtaining crude dihydrochloride in the form of an amorphous solid of a bright yellow color (10.420 g). containing residual solvent.

Racemic dihydrochloride (10.4 g) was separated into two enantiomers by preparative chiral HPLC. using a preparatory column Syga1rak ΑΌ (20 μm) with 50: 50: 0.1 acetonitrile: methanol: isopropylamine as the mobile phase in three batches. The alpha value was 3.1 and separation by initial threshold was observed for all 3 downloads. There was no overlapping fraction and both enantiomers (as free bases) were isolated. at> 99.8 excluding errors each.

(2H) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H.8H-2a.5.8a-triazacenaphthylene-3.8-dione (first eluting component): (3.30 g. Solid light - beige color. chiral HPLC: 100% excluding error).

M8 (E8 +) t / ζ 302 (MH ⁺ ).

Rotation of the plane of polarization: alpha Ό = -120 ° (C = 1.00. Methanol. 21.8 ° C).

(2H) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H.8H-2a.5.8a-triazacenaphthylene-3.8-dione (second eluting component): (3.30 g. Solid light beige color. chiral HPLC: 99.8% excluding error).

M8 (E8 +) t / ζ 302 (MH ⁺ ).

Rotation of the plane of polarization: alpha Ό = 122 ° (C = 1.00. Methanol. 21.8 ° C).

(k) Target compound.

(2H) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H.8H-2a.5.8a-triazacenaphthylene-3.8-dione (100 mg. 0.332 mmol) was mixed with [1.3] oxathiolo [5.4-c] pyridine-6-carbaldehyde (for the synthesis see \ UO 2004058144. Example 61) (45 mg. 0.811 equiv.) In a mixture of chloroform: methanol (9: 1. Vol.: About .. 5 ml) at ambient temperature for 2 hours; the mixture was then treated with sodium triacetoxyborohydride (211 mg. 3.0 equiv.) with vigorous stirring at ambient temperature for 30 minutes. The mixture was quenched by the addition of a saturated aqueous solution of sodium bicarbonate (1 ml). An ESM (10 ml) was added and vigorous stirring was continued for 10 min followed by phase separation (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (eluting with 0-12% (2 M ΝΗ ₃ in MeOH) in an ESM). The appropriate fractions were combined and evaporated under reduced pressure and dried on a vacuum line over the weekend. getting the free base of the target compound in the form of a light yellow foam (70 mg. 44.3%)

M8 (E8 +) t / ζ 453 (MJ).

Ή NMR (SBS1z) 8.00 (1Η. S). 7.82 (1H. S). 7.77 (1H. D. 1 = 9.7 Hz). 7.18 (1Η. S). 6.39 (1H. D. 1 = 9.7 Hz). 5.73 (2H. S). 5.03 (1H. M). 4.55 (1H, dd, 1 = 12.5 Hz. 4.6 Hz). 4.38 (1H. Dd. 1 = 12.5 Hz. 9.2 Hz). 3.80 (2H, s). 3.13 (1H. Dd. 1 = 12.9 Hz. 3.5 Hz). 2.93 (1H, m). 2.70 (1H. Dd. 1 = 12.9 Hz. 9.0 Hz). 2.67 (1H, m). 2.50 (1N.m). 2.33 (1H. Dt. 1 = 11.4 Hz. 2.6 Hz). 2.25 (1H. Dt. 1 = 11.4 Hz. 2.6 Hz). 1.85 (3H. M). 1.36 (2H. M).

Treatment of the above free base (70 mg) in an ESM (1 ml) 1 eq. 1 M ΗΟ in diethyl ether gave. after removal of solvents under reduced pressure. target compound in the form of an amorphous solid, light yellow brown (75 mg).

M8 (E8 +) t / ζ 453 (MH ⁺ ).

- 41 015821

Example 17A (28) -2 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

(2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione (for preparation see Example 16A (]) (100 mg, 0.332 mmol) was stirred with [1,3] oxathiolo [5,4s] pyridine-6-carbaldehyde (for synthesis see VO 2004058144, example 61) (45 mg, 0.811 equiv.) In a mixture chloroform: methanol (9: 1, v: v, 5 ml) at ambient temperature for 2 hours; the mixture was then treated with sodium triacetoxyborohydride (211 mg, 3.0 equiv.) with vigorous stirring at ambient temperature for 30 minutes The mixture was quenched by the addition of a saturated aqueous solution of bicarbo sodium natrate (1 ml), ISM (10 ml) was added and vigorous stirring was continued for 10 min followed by phase separation (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (2 M ΝΗ ₃ in MeOH) in the ISM.The corresponding fractions were combined and evaporated under reduced pressure and dried on a vacuum line over the weekend to give the free base of the target compound in the form of a light yellow foam (91 mg, 61%).

M8 (E8 +) t / ζ 453 (MH ⁺ ).

¹ H NMR (SIS _1-3 ) (identical to that for the (2K) enantiomer, Example 16A) 8.00 (1H, s), 7.82 (1H, s), 7.77 (1H, d, 1 = 9.7 Hz), 7.18 (1H, s), 6.39 (1H, d, 1 = 9.7 Hz), 5.73 (2H, s), 5.03 (1H, m), 4.55 ( 1H, dd, 1 = 12.5 Hz, 4.6 Hz), 4.38 (1H, dd, 1 = 12.5 Hz, 9.2 Hz), 3.80 (2H, s), 3.13 (1H, dd, 1 = 12.9 Hz, 3.5 Hz), 2.93 (1H, m), 2.70 (1H, dd, 1 = 12.9 Hz, 9.0 Hz), 2, 67 (1H, m), 2.50 (1H, m), 2.33 (1H, dt, 1 = 11.4 Hz, 2.6 Hz), 2.25 (1H, dt, 1 = 11.4 Hz, 2.6 Hz), 1.85 (3H, m), 1.36 (2H, m).

Treatment of the indicated free base in IMS (1 ml) 1 eq. 1 M HC1 in diethyl ether gave, after removal of the solvents under reduced pressure, the target compound in the form of a yellow amorphous solid (95 mg).

M8 (E8 +) t / ζ 453 (MH ⁺ ).

Example 18. 2 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione hydrochloride

CXX

Racemic 2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione (for preparation see Example 16A (])) (400 mg, 1.327 mmol) was mixed with [1,3] oxathiolo [5,4-c] pyridine-6-carbaldehyde (for synthesis see VO 2004058144, Example 61) (200 mg, 0.9 equiv.) In a mixture of chloroform: methanol (9: 1 vol.: Vol., 15 ml) at ambient temperature for 30 minutes; the mixture was then treated with sodium triacetoxyborohydride (844 mg, 3.0 equiv.) with vigorous stirring at ambient temperature for 30 minutes. The reaction was quenched by the addition of a saturated aqueous sodium bicarbonate solution (5 ml) and the mixture was stirred at ambient temperature for 5 minutes. The organic phase was separated, dried over anhydrous No. 8O.- | and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 0-12% (2 M ammonia in methanol) in an ISM, the corresponding fractions were combined and evaporated under reduced pressure to obtain the free base (racemic) of the target compound in the form of a light yellow foam (290 mg , 46.8%).

M8 (E8 +) t / ζ 453 (MH ⁺ ).

¹ H NMR (SIS _1-3 ) (identical to that for homochiral samples (Example 16A and 17A), except for position ΝΗ) 8.00 (1H, s), 7.82 (1H, s), 7.77 (1H, d , 1 = 9.7 Hz), 7.18 (1H, s), 6.39 (1H, d, 1 = 9.7 Hz), 5.73 (2H, s), 5.03 (1H, m ), 4.55 (1H, dd, 1 = 12.5 Hz, 4.6 Hz), 4.38 (1H, dd, 1 = 12.5 Hz, 9.2 Hz), 3.80 (2H, s), 3.13 (1H, dd, 1 = 12.9 Hz, 3.5 Hz), 2.93 (1H, m), 2.70 (1H, dd, 1 = 12.9 Hz, 9, 0 Hz), 2.67 (1H, m), 2.50 (1H, m), 2.33 (1H, dt, 1 = 11.4 Hz, 2.6 Hz), 2.25 (1H, dt , 1 = 11.4 Hz, 2.6 Hz), 1.85 (2H, m), (ΝΗ under the NOI peak at 1.70), 1.36 (2H, m).

- 42 015821

The free base (290 mg) was dissolved in an ESM (5 ml) and treated with 1 equiv. 1 M HC1 in diethyl ether. Evaporation of the solvents under reduced pressure gave the target compound in the form of a pale yellow amorphous solid (281 mg).

M8 (E8 +) t / ζ 453 (MH ⁺ )

Example 16B (2H) -2 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione benzoate.

Example 17B (28) -2 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione benzoate.

Racemic 2 - ({4 - [([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-3H, 8H-2a, 5, 8a-triazacenaphthylene-3,8-dione hydrochloride, 200 mg, was separated into two enantiomers by preparative chiral HPLC (using a preparative column Syga1rack ^, (5 μm) 21x250 mm) with 1: 1 acetonitrile (containing 0.1% isopropylamine) and acetonitrile (containing 0.1% TEM) as a mobile phase.

(2H) -2 - {{4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a 5,8a-triazacenaphthylene-3,8-dione (first eluting component): (81 mg).

Rotation of the plane of polarization: {alpha} P at 23.9 ° C = -85.58 ° (C = 798 in MeOH).

M8 (E8 +) t / ζ 302 (MH ⁺ ).

The free base was dissolved in methanol and treated with benzoic acid (1 eq.). Evaporation of the solvents under reduced pressure gave the product (Example 16B) in the form of benzoate.

(2H) -2 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a 5.8 a-triazacenaphthylene-3,8-dione (second eluting component): (76 mg).

Rotation of the plane of polarization: {alpha} P at 23.9 ° C = 84.9 ° (C = 798 in MeOH).

M8 (E8 +) t / ζ 302 (MH ⁺ ).

The free base was dissolved in methanol and treated with benzoic acid (1 eq.). Evaporation of the solvents under reduced pressure gave the product (Example 17B) in the form of benzoate.

Example 19A (2H) -2 - ({4 - [(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1 piperidinyl} methyl) -1,2-dihydro 3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

(2H) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione (for preparation see Example 16A (1)) (600 mg, 1.991 mmol), 2,3-dihydro [1,4] oxathiino [2,3c] pyridin-7-carbaldehyde (for synthesis see \ O 2004058144, Example 60) (325 mg, 0.900 equiv.) And 20 μl of acetic acid were stirred in a mixture of chloroform: methanol (9: 1, vol: vol., 30 ml) at ambient temperature for 2 hours; the mixture was then treated with sodium triacetoxyborohydride (1.266 g, 3.0 eq.) with vigorous stirring at ambient temperature for 30 minutes. The mixture was quenched by the addition of a saturated aqueous solution of sodium bicarbonate (6 ml). An ESM (60 ml) was added and vigorous stirring was continued for 10 min followed by phase separation (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (eluting with 0-12% (2 M ΝΠ ₃ in MeOH) in an ESM.

The appropriate fractions were combined and evaporated under reduced pressure and dried in vacuo overnight to give the free base of the title compound as a pale yellow amorphous solid (658 mg).

M8 (E8 +) t / ζ 467 (MH ⁺ ).

Ή NMR (СРС1 ₃ , 400 MHz) δ 1.25-1.40 (2Н, m), 1.80-1.90 (2Н, m), 2.20-2.30 (1Н, m), 2 30-2.40 (1H, m), 2.45-2.55 (1H, m), 2.65-2.75 (2H, m), 2.90-2.95 (1H, m) , 3.10-3.20 (3H, m), 3.75 (2H, s), 4.35-4.45 (3H, m), 4.50-4.60 (1H, dd), 5 , 00-5.10 (1H, m), 6.40 (1H, d), 7.00 (1H, s), 7.75 (1H, d), 7.85 (1H, s), 8, 05 (1H, s).

The free base (650 mg, 1.393 mmol) was suspended in a dry ESM (10 ml) and a solution of 1 M hydrogen chloride in diethyl ether (1393 μl, 1,000 equiv.) Was added. The system was left sealed and shaken for 1 min, then the solvents were removed under reduced pressure and the residue was dried in vacuo to give the title compound as a yellow amorphous solid (682 mg).

- 43 015821

Example 20. 2 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro -3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride.

Example 19B (2K) -2 - ({4 - [(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1piperidinyl} methyl) -1,2-dihydro 3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione trifluoroacetate.

Example 21 (28) -2 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1 piperidinyl} methyl) -1,2- dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione

Racemic 2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione (for preparation see Example 16A (])) (360 mg, 1.195 mmol) was mixed with

2,3-dihydro [1,4] oxathiino [2,3-c] pyridine-7-carbaldehyde (for synthesis see XVO 2004058144, Example 60) (195 mg, 0.9 equiv.) In a mixture of chloroform: methanol (9: 1, vol: vol., 15 ml) at ambient temperature for 30 min; the mixture was then treated with sodium triacetoxyborohydride (760 mg, 3.0 equiv.) with vigorous stirring at ambient temperature for 30 minutes. The reaction was quenched by the addition of a saturated aqueous sodium bicarbonate solution (5 ml) and the mixture was stirred at ambient temperature for 5 minutes. The organic phase was separated, dried over anhydrous No. 8O ₄ and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 0-12% (2 M ammonia in methanol) in an ESM. The appropriate fractions were combined and evaporated under reduced pressure to obtain the free base of the target compound in the form of a light yellow foam (235 mg, 42% )

NMR and bC-M8 identical to the product of example 19A.

The free base (225 mg) was dissolved in an ESM (5 ml) and treated with 1 equiv. 1 M HC1 in diethyl ether. Evaporation of the solvents under reduced pressure gave the target compound (Example 20) in the form of a pale yellow amorphous solid (224 mg).

M8 (E8 +) t / ζ 467 (MH ⁺ ).

The target racemic hydrochloride (Example 20), 80 mg, was separated into two enantiomers by preparative chiral HPLC (using a Syra1rack preparative column (5 μm) 21x250 mm) with 2: 2: 1 methanol: acetonitrile: tert-butanol (containing 0.1% isopropylamine) as a mobile phase.

(2K) -2 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione (first eluting component): (31 mg).

M8 (E8 +) t / ζ 467 (MH ⁺ ).

2K material had a purity of 98.7%; further purification was carried out by reverse phase HPLC on a KgotakI S-18 column 5 μm (21x250 mm) with elution with a 9: 1 mixture of water (+ 0.1% TEM) and acetonitrile (+ 0.1% TEM) (3 runs) s obtaining ditrifluoroacetate (example 19B).

(2K) -2 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione (second eluting component): (32 mg) (Example 21). The stereochemistry of this compound was determined by x-ray crystallography using a small molecule.

M8 (E8 +) t / ζ 467 (MH ⁺ ).

Example 22 2 - ({4 - [(2,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro 3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Racemic 2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione (for preparation see Example 16A (])) (50 mg, 0.166 mmol) was stirred in a 9: 1 v: v mixture. chloroform: methanol (2 ml) with 2,3-dihydro [1,4] dioxino [2,3-s] pyridin-7-carbaldehyde (for synthesis see ^ No. O 2004058144, example 2 (s) or VO 03 / 087098, example 19 (ά)) (28 mg, 1.0 equiv.) At ambient temperature for 30 minutes, then the mixture was treated with sodium triacetoxyborohydride (105 mg, 3.0 equiv.) With vigorous stirring. After another 25 minutes of stirring, the reaction

- 44 015821 the mixture was quenched by the addition of a saturated aqueous solution of sodium bicarbonate (2 ml), diluted with dichloromethane and vigorously stirred at ambient temperature for 20 minutes. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure to give an orange gum; it was purified by silica gel column chromatography (eluting with 0-12% (2 M ΝΉ ₃ in MeOH) in an ESM). The appropriate fractions were combined and evaporated under reduced pressure to give the free base of the target compound in the form of a cream-colored amorphous solid (30 mg, 40%).

M8 (E8 +) t / ζ 451 (MH ⁺ ).

Ή NMR (C1) _; O1)) δ 7.98 (1H, s), 7.88 (1H, d, 1 = 9.7 Hz), 7.77 (1H, s), 6.94 (1H, s), 6.37 (1H, d, 1 = 9.7 Hz), 5.12 (1H, m), 4.43 (2H, m), 4.35 (2H, m), 4.29 (2H, m), 3 , 73 (2H, s), 3.07 (1H, m), 3.03 (1H, m), 2.83 (1H, dd, 1 = 13.2 Hz, 8.3 Hz), 2.70 (1H, m), 2.44 (1H, m), 2.26 (1H, dt, 1 = 11.6 Hz, 2.4 Hz), 2.18 (1H, dt, 1 = 11.6 Hz 2.4 Hz), 1.85 (2H, m), 1.33 (2H, m).

The free base was dissolved in ESM (1 ml) and treated with a solution of 1 M hydrogen chloride in diethyl ether (67 μl, 1.0 equiv.); the vessel was sealed and left at ambient temperature for 5 min, then the solvents were removed under reduced pressure to obtain the target compound (20 mg; part of the product was lost due to spraying upon evaporation of the solvents).

M8 (E8 +) t / ζ 451 (MH ⁺ ).

Example 23. (1K) -1 - ({4 - [(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -4-methyl-1 piperidinyl} methyl) -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9-dione hydrochloride

(a) 1,1-Dimethylethyl-4-methyl-4 - ({[((phenylmethyl) oxy] carbonyl} amino) -1-piperidinecarboxylate.

A solution of 1 - {[(1,1-dimethylethyl) oxy] carbonyl} -4-methyl-4-piperidinecarboxylic acid (12.092 g, 49.7 mmol) in toluene (300 ml) was treated with triethylamine (13.85 ml, 99 mmol) ) and then diphenylphosphoryl azide (21.42 ml, 99 mmol), was heated to 90 ° C for 2 h (bubble formation was observed), after which it was treated with benzyl alcohol (10.34 ml, 99 mmol). The reaction mixture was then heated at 90 ° C for another 18 h, then cooled, treated with saturated aqueous sodium bicarbonate (500 ml), the organic extracts were separated and the aqueous layer was extracted with diethyl ether (200 ml), the combined organic extracts were dried (MD8O ₄ ), filtered, evaporated, chromatographed on a column (0-50% ethyl acetate: 40-60 petroleum ether, Κί = 0.4 in 4: 1 ethyl acetate: 4060 petroleum ether) to give the product in the form of a clear oil (15.473 g, 89%).

(b) (4-Methyl-4-piperidinyl) phenylmethylcarbamate.

A solution of 1,1-dimethylethyl-4-methyl-4 - ({[((phenylmethyl) oxy] carbonyl} amino) -1-piperidinecarboxylate (15.473 g, 44.4 mmol) in an ESM (50 ml) under argon at ambient temperature the medium was treated with trifluoroacetic acid (50 ml, 649 mmol) and stirred at ambient temperature for 0.5 h. The reaction mixture was then evaporated, dissolved in water (200 ml), washed with diethyl ether (3x200 ml). The aqueous phase was then basified with solid potassium carbonate, extracted with 20% methanol / ESM (3x200 ml), these organic extracts were then dried (MD8O ₄ ), filtered and evaporated to give the product as a yellow oil (6.327 g, 57%).

M8 (E8 +) t / ζ 249 (MH ⁺ ).

(c) (1 - {[(2K) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridin-2 -yl] methyl} -4methyl-4-piperidinyl) phenylmethylcarbamate.

A solution of (18) -1- (hydroxymethyl) -1,2,5,6-tetrahydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9dione (for obtaining see Example 5A (d)) (1.494 g, 6.78 mmol) in an ESM (50 ml) at 0 ° C under argon was treated with triethylamine (1.7 ml, 12.20 mmol) and then methanesulfonyl chloride (0.800 ml, 10 , 27 mmol) and then allowed to warm to ambient temperature and stirred at ambient temperature for 1 h. The reaction mixture was then treated with saturated aqueous bicarbonate solution (200 ml) and the mixture was extracted with ESM (3x200 ml). The combined organic solvents were then dried (Md8O _4), filtered and evaporated to give the crude mesylate (2.082 g, 6.987 mmol, crude yield 103%). The mesylate was dissolved in dry acetonitrile (30 ml) and then treated with pyridine (1.097 ml, 13.57 mmol) and a solution of (4-methyl-4 piperidinyl) phenylmethyl carbamate (3.164 g, 12.74 mmol) in dry acetonitrile (20 ml) and heated under reflux (heating block 95 ° C) for 6 hours. The reaction mixture was then evaporated, treated with saturated aqueous NaHCO ₃ solution (200 ml) and the mixture was extracted with ESM (3x200 ml). The combined organic solvents were then dried (Md8O _4), filtered and evaporated to give crude product in the form of an orange solid which was then chromatographed (0-10% methanol / OSM, W = 0.5 in 10% methanol / OCM) to give yellow solid product (1.848 g, 61%).

M8 (E8 +) t / ζ 451 (MH ⁺ ).

- 45 015821 (ά) (1K) -1 - [(4-amino-4-methyl-1-piperidinyl) methyl] -1,2,5,6-tetrahydro-4H, 9H-imidazo [1,2,3 woo] -

1,8-naphthyridine-4,9-dione.

Solution (1 - {[(2K) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridin-2yl] methyl } -4-methyl-4-piperidinyl) phenylmethylcarbamate (1.848 g, 4.10 mmol) in ethanol at ambient temperature under argon was treated with palladium-carbon (10% paste) (0.462 g, 4.34 mmol) (20% wt./weight.) and stirred under 1 atm of hydrogen for 2 h, the reaction mixture was filtered through a thin layer of KleGeCiNg. eluting with ethanol (100 ml). The filtrate was treated with palladium on charcoal (10% paste) (0.462 g, 4.34 mmol) and stirred at less than 1 atm of hydrogen for 18 hours. The reaction mixture was filtered through a thin layer of K1e18e1diig, eluting with ethanol (500 ml) and the filtrate was then evaporated obtaining the product in the form of a yellow solid (1.294 g, 100%).

M8 (E8 +) t / ζ 317 (MH ⁺ ).

(f) (1K) -1 - [(4-Isocyanato-4-methyl-1-piperidinyl) methyl] - 1,2,5,6-tetrahydro-4H, 9H-imidazo [1,2,3y] -1 , 8-naphthyridine-4,9-dione.

Solution (1K) -1 - [(4-amino-4-methyl-1-piperidinyl) methyl] -1,2,5,6-tetrahydro-4H, 9H-imidazo [1,2,3y] -1,8 naphthyridine-4,9-dione (1.294 g, 4.09 mmol) in an ESM (30 ml) in an argon atmosphere at ambient temperature was treated with triethylamine (0.684 ml, 4.91 mmol), then di-tert-butyl bicarbonate (1.045 ml, 4.50 mmol) and finally 4-dimethylaminopyridine (0.050 g, 0.409 mmol) and stirred at ambient temperature for 1 h. The reaction mixture was treated with aqueous sodium bicarbonate (100 ml) and extracted with ESM (3x200 ml). The combined organic fractions were dried (MgSO ₄ ), filtered and evaporated to give the crude product in the form of a yellow solid, which was then chromatographed (0-10% methanol / ESM, CT = 0.5 in 10% methanol / ESM), receiving the product in the form of a white solid (561 mg, 40%).

M8 (E8 +) t / ζ 343 (MH ⁺ ).

(ί) (1K) -1 - [(4-amino-4-methyl-1-piperidinyl) methyl] -1,2,5,6-tetrahydro-4H, 9H-imidazo [1,2,3-y] -1.8 naphthyridine-4,9-dione.

The solution of (1K) -1 - [(4-isocyanato-4-methyl-1-piperidinyl) methyl] - 1,2,5,6-tetrahydro-4H, 9 Nimidazo [1,2,3-y] -1,8 -naphthyridine-4,9-dione (561 mg, 1.638 mmol) in THE (10 ml) and water (10.00 ml) at ambient temperature was treated with sodium hydroxide (5 ml, 10.00 mmol) and stirred at ambient temperature medium for 1 h. The reaction mixture was then treated with concentrated HCl (5 ml, 12 M) and stirred at ambient temperature for 18 h, then evaporated. The resulting solid was treated with methanol (20 ml) and then the solvent was decanted from the solid and evaporated to give the product in the form of a crude green solid (687 mg, 108%).

M8 (E8 +) t / ζ 317 (MH ⁺ ).

(e) Ν- (1 - {[(2K) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridine -2-yl] methyl} 4-methyl-4-piperidinyl) -2,2,2-trifluoroacetamide.

Solution (1K) -1 - [(4-amino-4-methyl-1-piperidinyl) methyl] -1,2,5,6-tetrahydro-4H, 9H-imidazo [1,2,3y] -1,8 naphthyridine-4,9-dione (687 mg, 1.765 mmol) in an ESM (20 ml) and triethylamine (1.476 ml, 10.59 mmol) at 0 ° C were treated with trifluoroacetic acid anhydride (0.299 ml, 2.118 mmol) and stirred at ambient temperature for 1 h. The reaction mixture was treated with saturated sodium bicarbonate solution (50 ml) and extracted with an ESM (3x100 ml). The combined organic solvents were then dried (MgSO ₄ ), filtered, evaporated to give the crude product in the form of an orange solid, which was then chromatographed (0-10% methanol / OSM, W = 0.4 in 10% methanol / ESM) obtaining the product in the form of a crude yellow solid (375 mg, 52%).

M8 (E8 +) t / ζ 413 (MH ⁺ ).

(H) Ν- (1 - {[(1K) -4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridin-1-yl ] methyl} -4methyl-4-piperidinyl) -2,2,2-trifluoroacetamide.

Solution No. (1 - {[(2K) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridin-2yl] methyl} -4-methyl-4-piperidinyl) -2,2,2-trifluoroacetamide (375 mg, 0.909 mmol) in 1,4-dioxane (20 ml) was treated with ΩΩΟ (248 mg, 1.091 mmol) at ambient temperature and then heated at 80 ° C. for 1 hour. The reaction mixture was then cooled to ambient temperature. The reaction mixture was treated with a saturated aqueous solution of K ₂ CO ₃ (5%, 100 ml), then an ESM (100 ml) and the mixture was filtered through Kieselguhr. The organic fraction was separated and the aqueous layer was extracted with ESM (2x100 ml). The combined organic solvents were then dried (MgSO ₄ ), filtered and evaporated to give the crude product in the form of a yellow oil.

Silica gel chromatography (0-10% methanolBCM, KE = 0.4 in 10% MeOH / OCM) gave the product in the form of a clear oil (171 mg, 46%).

M8 (E8 +) t / ζ 411 (MH ⁺ ).

- 46 015821 (ί) (1K) -1 - [(4-amino-4-methyl-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] - 1,8naphthyridine-4,9-dione.

No. (1 - {[(1K) -4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridin-1-yl] methyl} - 4-methyl4-piperidinyl) -2,2,2-trifluoroacetamide (171 mg, 0.417 mmol) was treated with a 7% potassium carbonate solution (450 mg in 2 ml of water / 5 ml of methanol) and stirred at ambient temperature for 2 h and then at 70 ° C for 18 h then it was evaporated and dissolved in 5% HeΟH / ^ CΜ (100 ml), filtered and purified 8CX (5 g, eluting with MeOH and then 0.5 M NH ₃ / HeΟN and then 2 M NН ₃ / ΟеΟН). The fractions containing the product were then evaporated to give the product in the form of a pink solid (60 mg, 46%)

M8 (E8 +) t / ζ 315 (MH ⁺ ).

(ί) Target connection.

Suspension (1K) -1 - [(4-amino-4-methyl-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-ϊ]] -

1,8-naphthyridine-4,9-dione (34 mg, 0.108 mmol) in chloroform (2 ml) and methanol (0.1 ml) at ambient temperature under argon atmosphere was treated with 2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7carbaldehyde (19.60 mg, 0.108 mmol) (for synthesis see νΟ2004058144, Example 60) and stirred for 2 hours. The solution was then treated with sodium triacetoxyborohydride (68.8 mg, 0.324 mmol) and stirred at ambient temperature for 0.5 h. The reaction mixture was then treated with saturated aqueous NaHC- ₃ solution (20 ml) and extracted with 20% methanol / OSM (3x100 ml). The combined organic extracts were dried (Mg ^ D filtered, evaporated and chromatographed (0-20% methanol / ESM, Κί = 0.4 in 15% methanol / ESM) to give the free base of the target compound as a light brown solid (32 mg, 0.067 mmol, 62%).

M8 (E8 +) t / ζ 517 (MH ⁺ ).

Ή NMR (SHS1 ₃ , 250 MHz) δ 1.14 (3H, s), 1.42-1.70 (4H, m), 2.30-2.45 (1H, m), 2.50-2 82 (4H, m), 3.053.22 (3H, m), 3.68 (2H, s), 4.28-4.48 (3H, m), 4.51-4.63 (1H, m) ), 4.96-5.11 (1H, m), 6.20-6.35 (2H, m), 7.04 (1H, s), 7.46-7.51 (2H, m), 8.00 (1H, s).

The free base in ^ СΜ / ΜеΟН 2: 1 (10 ml) was treated with 1 M HC1 in diethyl ether and then evaporated to give the desired hydrochloride in the form of a white solid (34 mg)

Example 24 (1K) -1 - ({4-Methyl-4 - [([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1.2 -dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

Suspension (1K) -1 - [(4-amino-4-methyl-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-ϊ]] -

1,8-naphthyridine-4,9-dione (26 mg, 0.083 mmol) (for preparation see Example 23 (1)) in chloroform (2 ml) and methanol (0.1 ml) at ambient temperature in the atmosphere argon was treated with [1,3] oxathiolo [5,4-c] pyridine-6-carbaldehyde (13.83 mg, 0.083 mmol) (for synthesis see νΟ2004058144, example 61) and stirred at ambient temperature for 2 h. The solution was then treated with sodium triacetoxyborohydride (52.6 mg, 0.248 mmol) and stirred at ambient temperature for 0.5 h. The reaction mixture was then treated with a saturated aqueous solution NaHCΟ ₃ (10 ml) and was extracted with a mixture of 20% methanol / ESM (3x50 ml). The combined organic fractions were dried (Μд8Ο ₄ ), filtered, evaporated and chromatographed (0-20% methanol / OSM, Κί = 0.3 in 15% methanol / ESM) to give the free base of the target compound in the form of a yellow solid (29 mg , 75%).

M8 (E8 +) t / ζ 466 (MH ⁺ ).

Ή NMR (SHS1 ₃ , 250 MHz) δ 1.14 (3H, s), 1.40-1.71 (4H, m), 2.30-2.46 (1H, m), 2.51-2 82 (4H, m), 3,083.22 (1H, m), 3.73 (2H, s), 4.28-4.42 (1H, m) 4.51-4.65 (1H, m) 4.92-5.09 (1H, m), 5.72 (2H, s), 6.20-6.34 (2H, m), 7.25 (1H, s), 7.50-7 51 (2H, m), 7.98 (1H, s).

The free base in ^ CΜ / HeΜH 2: 1 (5 ml) was treated with 1 M HCl in diethyl ether and then evaporated to give the desired hydrochloride.

Example 25. (2K) -2 - ({4 - [(2,1,3-Benzothiadiazol-5-ylmethyl) amino] - 1-piperidinyl} methyl) -1,2 dihydro-3H, 8H-2a, 5.8a triazacenaphthylene-3,8-dione hydrochloride

- 47 015821 (2K) -2 - [(4-amino-1-piperidinyl) methyl] - 1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione (50 mg, 0.166 mmol) (for preparation see Example 16 (])) and 2,1,3-benzothiadiazole-5-carbaldehyde (25 mg, 0.918 equiv.) were mixed in a 9: 1 v: v mixture. chloroform: methanol (1 ml) over 2.5 hours. Then, sodium triacetoxyborohydride (105 mg, 3,000 equiv.) was added in one part and the mixture was vigorously stirred at ambient temperature for 30 minutes. Then a saturated aqueous solution of sodium bicarbonate (0.5 ml) was added, then dichloromethane (10 ml) and the mixture was vigorously stirred at ambient temperature for 10 min and the phases were separated (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (eluting with 0-12% (2 M ΝΉ ₃ in MeOH) in an ISM). The appropriate fractions were combined and evaporated under reduced pressure to give the free base of the target compound in the form of a yellow solid (41 mg).

M8 (E8 +) t / ζ 450 (MH ⁺ ).

Ή NMR (SIS1 ₃ ) δ 7.95 (1H, d, 1 = 9.0 Hz), 7.90 (1H, s), 7.83 (1H, s), 7.77 (1H, d, 1 = 9.7 Hz), 7.61 (1H, dd, 1 = 9.2 Hz, 1.8 Hz), 6.39 (1H, d, 1 = 9.7 Hz), 5.03 (1H, m), 4.56 (1H, dd, 1 = 12.5 Hz, 4.6 Hz), 4.39 (1H, dd, 1 = 12.5 Hz, 9.2 Hz), 3.98 (2H , s), 3.14 (1H, dd, 1 = 13.2 Hz, 3.5 Hz), 2.94 (1H, m broad), 2.69 (2H, m), 2.56 (1H , m), 2.34 (1H, dt, 1 = 11.4 Hz, 2.6 Hz), 2.25 (1H, dt, 1 = 11.4 Hz, 2.6 Hz), 1.89 ( 2H, m), (ΝΉ under the peak of the NOI 1.48), 1.37 (2H, m).

The free base (35 mg, 0.078 mmol) was dissolved in ISM (1 ml) and hydrogen chloride (1.0 M) in diethyl ether (78 μl, 1.0 eq.) Was added. The system was sealed and shaken at ambient temperature for 1 min, then the solvents were removed under reduced pressure to obtain the desired compound in the form of a yellow solid (38 mg).

M8 (E8 +) t / ζ 450 (MH ⁺ ).

Example 26. (2K) -2 - [(4 - {[(7-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1, 2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

(2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione (50 mg, 0.166 mmol) ( for the preparation, see example 16 (])) and 7-fluoro-2,3-dihydrobenzo [1,4] dioxin6-carboxaldehyde (28 mg, 0.926 equiv.) (for the synthesis, see VO 2002056882, example 23 (a )) was mixed in a mixture of 9: 1 vol.: about. chloroform: methanol (1 ml) over 2.5 hours. Then, sodium triacetoxyborohydride (105 mg, 3,000 equiv.) was added in one part and the mixture was vigorously stirred at ambient temperature for 30 minutes. Then a saturated aqueous solution of sodium bicarbonate (0.5 ml) was added, then dichloromethane (10 ml) and the mixture was vigorously stirred at ambient temperature for 10 min and the phases were separated (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (eluting with 0-12% (2 M ΝΉ ₃ in MeOH) in an ISM). The appropriate fractions were combined and evaporated under reduced pressure to give the free base of the target compound in the form of a white solid (48 mg).

M8 (E8 +) t / ζ 468 (MH ⁺ ).

Ή NMR (SIS1 ₃ ): δ 7.82 (1H, s), 7.76 (1H, d, 1 = 9.7 Hz), 6.79 (1H, d, 1 = 7.2 Hz), 6 , 57 (1H, d, 1 = 10.5 Hz), 6.38 (1H, d, 1 = 9.7 Hz), 5.03 (1H, m), 4.54 (1H, dd, 1 = 12.5 Hz, 4.4 Hz), 4.38 (1H, dd, 1 = 12.5 Hz, 9.4 Hz), 4.23 (4H, m), 3.71 (2H, s), 3.12 (1H, dd, 1 = 12.9 Hz, 3.3 Hz), 2.92 (1H, m), 2.68 (2H, m), 2.68 (2H, m), 2, 47 (1H, m),

2.33 (1H, dt, 1 = 11.4 Hz, 2.6 Hz), 2.24 (1H, dt, 1 = 11.4 Hz, 2.6 Hz), 1.83 (2H, m), ( ΝΉ under the peak of NOI 1.50),

1.33 (2H, m).

The free base (48 mg, 0.103 mmol) was dissolved in ISM (1 ml) and hydrogen chloride (1.0 M) in diethyl ether (103 μl, 1.0 eq.) Was added. The system was sealed and shaken at ambient temperature for 1 min, then the solvents were removed under reduced pressure to obtain the desired compound in the form of a yellow solid (55 mg).

M8 (E8 +) t / ζ 468 (MH ⁺ ).

- 48 015821

Example 27. (2K) -2 - ({4 - [(3,4-Dihydro-2H- [1,4] oxathiepino [2,3-c] pyridin-8-ylmethyl) amino] -1piperidinyl} methyl) - 1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

(2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione (50 mg, 0.166 mmol) ( for preparation see Example 16 (])) and 3,4-dihydro-2H- [1,4] oxathiepino [2,3c] pyridin-8-carbaldehyde (29 mg, 0.895 equiv.) (can be obtained analogously to synthesis

2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-carbaldehyde (^ O 2004058144, Example 60), but with dibromoethane replaced by dibromopropane) was stirred in a 9: 1 v: v mixture. chloroform: methanol (1 ml) over 2.5 hours. Sodium triacetoxyborohydride (105 mg, 3,000 equiv.) was then added in one portion and the mixture was vigorously stirred at ambient temperature for 30 minutes. Then, saturated aqueous sodium bicarbonate solution (0.5 ml) was added, then dichloromethane (10 ml), the mixture was vigorously stirred at ambient temperature for 10 min, and the phases were separated (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (eluting with 0-12% (2 M ΝΗ ₃ in MeOH) in an ESM. The appropriate fractions were combined and evaporated under reduced pressure to give the free base of the target compound as a pale yellow solid (65 mg).

Mg (E8 +) t / ζ 481 (MH ⁺ ).

Ή NMR (ϋϋα ₃ ): δ 8.12 (1H, s), 7.82 (1H, s), 7.76 (1H, d, 1 = 9.7 Hz), 7.17 (1H, s) 6.38 (1H, d, 1 = 9.7 Hz), 5.03 (1H, m), 4.55 (1H, dd, 1 = 12.5 Hz, 4.5 Hz), 4.37 (3H, m), 3.79 (2H, s), 3.13 (3H, m), 2.94 (1H, m), 2.69 (2H, m), 2.52 (1H, m) 2.30 (4H, m), 1.86 (3H, m), 1.37 (2H, m).

The free base (60 mg, 0.125 mmol) was suspended in a dry ESM (1 ml) and a solution of 1 M hydrogen chloride in diethyl ether (125 μl, 1,000 equiv.) Was added. The system was left sealed and shaken for 1 min, then the solvents were removed under reduced pressure and the residue was dried on a vacuum line to obtain the desired compound in the form of a yellow amorphous solid (64 mg).

Mg (E8 +) t / ζ 481 (MH ⁺ ).

Example 28. (2K) -2 - ({4 - [([1,3] Oxathiolo [4,5-s] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

(a) [1,3] Oxathiolo [4,5-s] pyridin-6-carbaldehyde.

The target compound was obtained by treatment:

(ί) [5 - ({[4- (methyloxy) phenyl] methyl} oxy) -4-oxo-1,4-dihydro-2-pyridinyl] methyl acetate (for synthesis see ^ O 2004058144, example 60 (c )) triphenylphosphine, diisopropylazodicarboxylate and benzyl alcohol to give {5 - ({[4- (methyloxy) phenyl] methyl} oxy) -4 - [(phenylmethyl) oxy] -2pyridinyl} methyl acetate;

(ίί) {5 - ({[4- (methyloxy) phenyl] methyl} oxy) -4 - [(phenylmethyl) oxy] -2-pyridinyl} methyl acetate trifluoroacetic acid and triethylsilane to give {5-hydroxy-4 - [( phenylmethyl) oxy] -2pyridinyl} methyl acetate trifluoroacetate;

(ίίί) {5-hydroxy-4 - [(phenylmethyl) oxy] -2-pyridinyl} methyl acetate trifluoroacetate 1,1,1-trifluoro-phenyl-Y - [(trifluoromethyl) sulfonyl] methanesulfonamide and triethylamine, obtaining (4- [ (phenylmethyl) oxy] -5 - {[(trifluoromethyl) sulfonyl] oxy} -2-pyridinyl) methyl acetate;

(ίν) (4 - [(phenylmethyl) oxy] -5- {[(trifluoromethyl) sulfonyl] oxy} -2-pyridinyl) methyl acetate (K) - (+) -

2,2-bis- (diphenylphosphino) -1,1-binaphthyl, palladium acetate and sodium 2-methyl-2-propanethiolate, obtaining {5 - [(1,1-dimethylethyl) thio] -4- [(phenylmethyl) hydroxy ] -2-pyridinyl} methyl acetate;

- 49 015821 (ν) {5 - [(1,1-dimethylethyl) thio] -4 - [(phenylmethyl) oxy] -2-pyridinyl} methyl acetate with palladium on carbon under 1 atm of hydrogen, obtaining {5 - [(1, 1-dimethylethyl) thio] -4-oxo-1,4-dihydro-2-pyridinyl} methyl acetate;

(νί) {5 - [(1,1-dimethylethyl) thio] -4-oxo-1,4-dihydro-2-pyridinyl} methyl acetate with concentrated hydrochloric acid to give 2- (hydroxymethyl) -5-mercapto-4 (1H ) -pyridinone;

(νίί) 2- (hydroxymethyl) -5-mercapto-4 (1H) -pyridinone with potassium carbonate and dibromomethane to give [1,3] oxathiolo [4,5-s] pyridin-6-ylmethanol, and (νίίί) [1 , 3] oxathiolo [4,5-c] pyridin-6-ylmethanol with manganese dioxide, to give the desired compound.

(B) Target compound.

(2B) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione (50 mg, 0.166 mmol) ( for preparation see Example 16 (])) and [1,3] oxathiolo [4,5-s] pyridin-6carbaldehyde (25 mg, 0.901 equiv.) were mixed in a 9: 1 v: v mixture. chloroform: methanol (1 ml) over 2.5 hours. Sodium triacetoxyborohydride (105 mg, 3,000 equiv.) was then added in one portion and the mixture was vigorously stirred at ambient temperature for 30 minutes. Then, saturated aqueous sodium bicarbonate solution (0.5 ml) was added, then dichloromethane (10 ml), the mixture was vigorously stirred at ambient temperature for 10 min, and the phases were separated (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (eluting with 0-12% (2 M ΝΉ ₃ in MeOH) in an ESM.

The appropriate fractions were combined and evaporated under reduced pressure to give the free base of the target compound in the form of a pale yellow amorphous solid (48 mg).

Ή NMR (CBC1 ₃ ) δ 8.22 (1H, s), 7.82 (1H, s), 7.76 (1H, d, 1 = 9.7 Hz), 6.80 (1H, s), 6.38 (1H, d, 1 = 9.7 Hz), 5.77 (2H, s), 5.03 (1H, m), 4.55 (1H, dd, 1 = 12.5 Hz, 4 , 6 Hz), 4.38 (1H, dd, 1 = 12.5 Hz, 9.4 Hz), 3.81 (2H, s), 3.13 (1H, dd, 1 = 13.0 Hz, 3.5 Hz), 2.93 (1H, m), 2.68 (2H, m), 2.49 (1H, m), 2.33 (1H, dt, 1 = 11.4 Hz, 2, 6 Hz), 2.24 (1H, dt, 1 = 11.4 Hz, 2.6 Hz), 1.84 (3H, m), (ΝΠ under the peak of NOV 1.66), 1.34 (2H, m).

M8 (E8 +) w / ζ 453 (MH ⁺ ).

The free base of the target compound (48 mg, 0.106 mmol) was suspended in a dry ESM (1 ml) and a solution of 1 M hydrogen chloride in diethyl ether (106 μl, 1,000 equiv.) Was added. The system was left sealed and shaken for 1 min, then the solvents were removed under reduced pressure and the residue was dried on a vacuum line to obtain the desired compound in the form of a yellow amorphous solid (48 mg).

M8 (E8 +) w / ζ 453 (MH ⁺ ).

Example 29. (2B) -2 - [(4- {[(3-Oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) methyl] amino } -1 piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione hydrochloride

(2B) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione (50 mg, 0.166 mmol) ( for preparation see Example 16 (])) and 3-oxo-3,4-dihydro-2H-pyrido [3,2 b] [1,4] thiazine-6-carboxaldehyde (29 mg, 0.90 equiv.) (for synthesis see \ UO 2003087098, example 301 (ά)) was stirred in a 9: 1 mixture of chloroform: methanol (1 ml) at ambient temperature for 3 hours, then sodium triacetoxyborohydride (105 mg, 3.00 eq) was added .). The mixture was stirred at ambient temperature for another 30 minutes, then a saturated aqueous solution of sodium bicarbonate (0.5 ml) was added and the organic phase was diluted with ESM (10 ml). The mixture was vigorously stirred for 10 minutes, then the organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The residue was suspended in an ESM (approximately 3 ml) + 1 drop of MeOH and purified by silica gel column chromatography (eluting with 0-12% (2 M ΝΉ ₃ in MeOH) in an ESM). The appropriate fractions were combined and evaporated to give the free base of the target compound in the form of a yellow amorphous solid.

Ή NMR (CBC1 ₃ ) δ 8.58 (1H, s. Broad), 7.83 (1H, s), 7.77 (1H, d, 1 = 9.7 Hz), 7.57 (1H, d, 1 = 7.8 Hz), 6.97 (1H, d, 1 = 7.8 Hz), 6.38 (1H, d, 1 = 9.7 Hz), 5.04 (1H, m) 4.55 (1H, dd, 1 = 12.5 Hz, 4.5 Hz), 4.38 (1H, dd, 1 = 12.5 Hz, 9.3 Hz), 3.82 (2H, s ), 3.47 (2H, s), 3.14 (1H, dd, 1 = 13.0 Hz, 3.5 Hz), 2.94 (1H, m), 2.69 (2H, m), 2.51 (1H, mt), 2.33 (1H, dt, 1 = 11.4 Hz, 2.4 Hz), 2.25 (1H, dt, 1 = 11.4 Hz, 2.4 Hz) , (ΝΉ under the peak of NOV 2.06), 1.85 (2H, m), 1.37 (2H, m).

M8 (E8 +) w / ζ 480 (MH ⁺ ).

- 50 015821

The free base of the target compound (43 mg, 0.090 mmol) was dissolved in an ESM (2 ml) and a solution of 1 M hydrogen chloride in diethyl ether was added. The system was left sealed and shaken for 1 minute, then the solvents were removed under reduced pressure and the residue was dried on the suction pipe to obtain the desired compound in the form of a yellow amorphous solid (38 mg).

M8 (E8 +) t / ζ 480 (MH ⁺ ).

The solvents were removed and the solid was dried in a desiccator (P2O5) overnight to give the product in the form of a white solid (51 mg, LCM8 and NMR corresponding to the product).

Example 30. (1K) -1 - ({4 - [(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

Suspension of (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8naphthyridine-4,9-dione dihydrochloride (for preparation see Example 5A (])) (60 mg, 0.161 mmol) in chloroform (2 ml) and methanol (0.100 ml) at ambient temperature under argon atmosphere was treated with triethylamine (0.067 ml, 0.482 mmol) and stirred at ambient temperature for 15 hours. The solution was then treated with 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (commercially available) (23.75 mg, 0.145 mmol) and stirred for another 30 minutes. The solution was then treated with sodium triacetoxyborohydride (102 mg, 0.482 mmol) and stirred at ambient temperature for 30 minutes, after after 30 minutes LBCM8 showed the presence of a certain amount of starting material, additional sodium triacetoxyborohydride (19 mg) was added and the reaction mixture stirred for 15 minutes Then it was treated with a saturated aqueous NaHCO3 solution (10 ml) and extracted with 20% methanol / ESM (3 km). The combined organic extracts were dried (Md8O _4), filtered, evaporated and chromatographed (0-20% methanol / SEM) to give the title compound as a yellow resin form, which is a free base (48 mg, 67%).

'|| NMR (SEST, 250 MHz) δ 1.28-1.51 (m, 2H), 1.75-1.99 (m, 2H), 2.13-2.38 (m, 2H), 2.41 -2.80 (m, 3H),

2.90-3.15 (m, 2H), 3.75 (s, 2H), 4.22 (s, 4H), 4.31-4.42 (m, 1H), 4.51-4, 62 (m, 1H), 4.90-5.08 (m, 1H), 6.20-6.32 (m, 2H), 6.81 (m, 2H), 6.84 (m, 1H) 7.42-7.53 (m, 2H).

M8 (E8 +) t / ζ 449 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of ESM. treated with 1 equiv. 1 M HCl in diethyl ether and then evaporated to give the title compound in the form of a mono-HCl salt (44 mg, 53%).

Bcm8 was consistent with the product.

Example 31. (1K) -1 - [(4- {[(8-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1-piperidinyl) methyl] - 1, 2-dihydro-4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9-dione hydrochloride

Suspension (1K) -1 - ({4 - [(1,2,3-benzothiadiazol-5-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H, 9H-imidazo [1,2,3 -y] -1,8-naphthyridine-4,9-dione dihydrochloride (for preparation see Example 5 (])) (50 mg, 0.134 mmol) in chloroform (2 ml) and methanol (0.100 ml) at ambient temperature media in an argon atmosphere was treated with triethylamine (0.056 ml, 0.402 mmol) and stirred at ambient temperature for 15 minutes. The solution was then treated with 8-fluoro-2,3-dihydro1,4-benzodioxin-6-carbaldehyde (for synthesis see \ UO 2007122258, example 8 (b)) (21.96 mg, 0.121 mmol) and stirred for another 30 min . The solution was treated with sodium triacetoxyborohydride (85 mg, 0.402 mmol) and stirred at ambient temperature for 30 minutes, after 30 minutes LBM8 showed that the starting material and the imine of the product remained. Therefore, an additional amount of sodium triacetoxyborohydride (40 mg) was added, the reaction mixture was stirred for another 30 minutes. After this time, bCM8 showed that the reaction was complete. The reaction mixture was then treated with a saturated aqueous NaHCO3 solution (10 ml) and extracted with 20% methanol / ESM (3x25 ml). The combined organic fractions were dried (Md8O _4), filtered, evaporated and chromatographed (0-20% methanol / OCM) to give the free base of the title compound (6 mg, 9.6%) in the form of a solid of light yellow color and a quantity of crude product (15 mg, 24%) in the form of a pale yellow solid, which was purified using an 8CX column to give an additional amount of the target compound in the form of a free base.

- 51 015821

Ή NMR (SPS1 ₃ , 250 MHz) δ 1.15-1.50 (m, 2H), 1.70-2.10 (m, 2H), 2.15-2.39 (m, 2H), 2 41-2.58 (m, 1H),

2.60-2.74 (2H, m), 2.85-3.11 (m, 1H), 3.11-3.15 (m, 1H), 3.69 (s, 2H), 4, 22-4.45 (m, 5H), 4.50-4.62 (m, 1H),

4.90-5.09 (m, 1H), 6.20-6.35 (m, 2H), 6.60-6.72 (m, 2H), 7.41-7.52 (m, 2H) )

M8 (E8 +) t / ζ 467 (MH ⁺ ).

The free base of the target compound was then treated with 1 equiv. 1 M HC1 in diethyl ether to give the title compound in the form of monohydrochloride (16.7 mg, 27.5%).

Bcm8 was consistent with the product.

Example 32. (1K) -1 - [(4 - {[(7-Chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl ) methyl] amino} -1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione dihydrochloride

In a 10 ml round bottom flask, (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine was combined -4,9-dione (for preparation see Example 5A (])) (80 mg, 0.266 mmol), 7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (for synthesis see \ UO 2003064421, example 15 (c)) (62.3 mg, 0.293 mmol) and sodium bicarbonate (100 mg, 1.190 mmol) in an ESM (4 ml ) and methanol (1 ml) to obtain a brown solution. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. After 15 hours, sodium triacetoxyborohydride (113 mg, 0.533 mmol) was added and the reaction mixture was stirred at 25 ° C. under nitrogen for 4 hours. The reaction mixture was adsorbed onto silica gel and purified using 0-10% MeOH / OCM (1% NH ₄ IT). LBM8 and ¹ H NMR of the product corresponded to the target compound in the form of a free base.

Ή NMR (Ό-4 MeOH, 400 MHz) δ 1.24-1.45 (m, 2H), 1.79-1.96 (m, 2H), 2.22-2.31 (m, 2H) 2.46-2.53 (m, 1H), 2.59-2.68 (m, 1H), 2.87-3.09 (m, 4H), 3.89 (s, 2H), 4 , 42-4.51 (m, 2H), 4.69 (s, 2H), 5.07-5.15 (m, 1H), 6.266.35 (m, 2H), 7.39 (s, 1H) ), 7.75-7.81 (m, 2H).

M8 (E8 +) t / ζ 497/499 (MH ⁺ ).

The free base of the target compound was suspended in 10% MeOH / OCM and treated with 1N. HCl, obtaining the target compound in the form of a salt of di-HCl (55 mg, 36.2%).

Example 33. (1K) -1 - [(4 - {[(4-Chloro-7-oxo-6,7-dihydro-1H-pyrimido [5,4-b] [1,4] oxazin-2-yl ) methyl] amino} -1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione

In a 10 ml round bottom flask, (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine was combined -4,9-dione (for preparation see Example 5A (])) (60 mg, 0.178 mmol), 4-chloro-7-oxo-6,7-dihydro-1H-pyrimido [5,4-b] [1,4] oxazine-2-carbaldehyde (for synthesis see \ UO 2008009700, example 124 (d)) (38 mg, 0.178 mmol) and sodium bicarbonate (150 mg, 1.78 mmol) in an ESM (5 ml ) and methanol (1 ml) to obtain a brown solution. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. After 15 hours, sodium triacetoxyborohydride (113 mg, 0.533 mmol) was added and the reaction mixture was stirred at 25 ° C. under nitrogen for 4 hours. The reaction mixture was adsorbed onto silica gel and purified using 0-20% MeOH / OCM (1% NH ₄ OH) to afford the title compound (4 mg, orange solid, 4.51%).

Ή NMR (SPS1 ₃ , 250 MHz) δ 1.28-1.51 (m, 2H), 1.75-1.99 (m, 2H), 2.13-2.38 (m, 2H), 2 41-2.80 (m, 3H),

2.90-3.15 (m, 2H), 3.75 (s, 2H), 4.31-4.42 (m, 1H), 4.51-4.62 (m, 1H), 4, 8 (s, 2H), 4.90-5.08 (m, 1H), 6.25-6.32 (m, 2H), 7.51-7.53 (m, 2H).

M8 (E8 +) t / ζ 498/500 (MH ⁺ ).

Example 34. (1K) -1 - [(4 - {[(7-Oxo-6,7-dihydro-1H-pyrimido [5,4-b] [1,4] thiazin-2-yl) methyl] amino } -1 piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione dihydrochloride

(a) [(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl) thio] ethyl acetate.

A solution of 5-bromo-2,4 (1H, 3H) -pyrimidinedione (15 g, 79 mmol) and ethyl mercaptoacetate (8.58 ml, 79 mmol) in OME (200 ml) was treated with tetrabutylammonium hydrosulfate (6.67 g, 19.64 mmol) and potassium carbonate (23.88 g, 173 mmol) and stirred at ambient temperature overnight.

- 52 015821

The solution was filtered and concentrated under reduced pressure to obtain the crude target compound in the form of a yellow oil, which foamed under reduced pressure.

M8 (E8 +) t / ζ 231.1 (MH ⁺ ).

(b) [(2,4-Dichloro-5-pyrimidinyl) thio] ethyl acetate.

Suspension of [(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl) thio] ethyl acetate (crude material) (18.19 g, 79 mmol) in phosphoric acid chloride (100 ml, 1073 mmol) treated with dimethylaniline (2.500 ml, 19.72 mmol) and the reaction mixture was heated under reflux and stirred for 2 hours. The solution was allowed to cool to ambient temperature and slowly poured onto ice to quench the excess phosphoric acid chloride. After quenching, the aqueous layer was extracted with CH ₂ Cl ₂ (3x). The organic layers were combined, dried over Na ₂ 8 O ₄ , filtered and concentrated under reduced pressure. The crude material was chromatographed using a gradient of 0-50% EJAc / hexanes. The product was isolated in the form of a dark yellow oil.

Ή NMR (400 MHz, chloroform-ά) ppm 1.22 (t, 1 = 7.07 Hz, 3H), 3.71 (s, 2H), 4.15 (d, 1 = 7.33 Hz, 1H ), 8.53 (s, 1H).

(c) [(4-amino-2-chloro-5-pyrimidinyl) thio] ethyl acetate.

A solution of [(2,4-dichloro-5-pyrimidinyl) thio] ethyl acetate (2.0 g, 7.49 mmol) in OME (75 ml) was treated with ammonia in isopropanol (7.49 ml, 14.97 mmol) in sealed test tube. The tube was closed and the reaction mixture was stirred at ambient temperature. After completion of the process, the solution was concentrated under reduced pressure and pumped to remove residual EME. The crude material was chromatographed using a 0-10% acetone / chloroform gradient. The product contained a small amount of cyclized material (which is the product of the next step). The product was isolated as a pale yellow solid.

M8 (E8 +) t / ζ 248.0 (MH ⁺ ).

(ά) 2-Chloro-1H-pyrimido [5,4-b] [1,4] thiazin-7 (6H) -one.

A suspension of [(4-amino-2-chloro-5-pyrimidinyl) thio] ethyl acetate (0.786 g, 3.17 mmol) in ethanol (50 ml) was heated at 70 ° C. Cesium carbonate (1.034 g, 3.17 mmol) was added and the solution was heated for another 5 minutes. A white solid precipitated from the solution almost immediately. The solution was concentrated under reduced pressure. The residue was dissolved in water and adjusted to pH 5 with 1N. HC1. The aqueous layer was extracted with CH ₂ Cl ₂ (2x). The organic layers were combined, dried over Na ₂ 8 O ₄ , filtered and concentrated under reduced pressure to give a light yellow solid.

M8 (E8 +) t / ζ 202.0 (MH ⁺ ).

(e) 2-Ethenyl-1H-pyrimido [5,4-b] [1,4] thiazin-7 (6H) -one.

2-Chloro-1H-pyrimido [5.4-b] [1.4] thiazin-7 (6H) -one (0.639 g, 3.17 mmol) was treated with tributyl vinyltin (1.388 ml, 4.76 mmol) and tetrakis- (triphenylphosphine) palladium (0) (0.293 g, 0.254 mmol) in 1,4-dioxane (4 ml) and toluene (4 ml) in a microwave ampoule. The reaction mixture was heated in a microwave reactor at 140 ° C for 20 minutes. The solution was diluted with E1OAc and washed with saturated No. ₁ HCO ₃ solution. The aqueous layer was extracted with E1OAc (2x). The organic solution was combined, dried over Na ₂ 8 O ₄ , filtered and concentrated under reduced pressure. The crude material was chromatographed using a gradient of 0-60% CH ₂ Cl ₂ / (CH ₂ Cl ₂ / MeOH / XH ₄ OH) (90: 10: 1). The product was isolated as a mixture of the desired product and triphenylphosphine. Pure material was obtained by trituration and washing with diethyl ether. The product was isolated in the form of an orange solid.

M8 (E8 +) t / ζ 194.0 (MH ⁺ ).

(1) 7-Oxo-6,7-dihydro-1H-pyrimido [5,4-b] [1,4] thiazine-2-carbaldehyde.

A solution of 2-ethenyl-1H-pyrimido [5,4-b] [1,4] thiazin-7 (6H) -one (0.262 g, 1.356 mmol) in a methanol / ESM mixture was cooled to -78 ° C and treated with ozone, until the solution turns blue. The solution was stirred at -78 ° C for an additional 5 minutes. Dimethyl sulfide (5.0 ml, 67.6 mmol) was added and the solution was allowed to warm to ambient temperature and was stirred overnight. The solution was concentrated on silica gel and the crude material was chromatographed using a gradient of 0-100% CH ₂ Cl ₂ / (CH ₂ Cl ₂ / MeOH / XH ₄ OH) (90: 10: 1). The product was isolated as a pale yellow solid.

M8 (E8 +) t / ζ 195.9 (MH ⁺ ).

(e) Target compound.

Suspension (1H) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8naphthyridine-4,9-dione (for production see Example 5A (])) (0.060 g, 0.179 mmol) in 1: 1 CH ₂ Cl ₂ / MeOH (10 ml) was treated with 7-oxo-6,7-dihydro-1H-pyrimido [5, 4-b] [1,4] thiazine-2 carbaldehyde (0.035 g, 0.179 mmol) and sodium bicarbonate (0.151 g, 1.793 mmol). An excess of Na ₂ 8 O ₄ was added and the reaction mixture was stirred at ambient temperature for 18 hours. Sodium triacetoxyborohydride (0.114 g, 0.538 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The solution was concentrated on silica gel and crude material

- 53 015821 chromatographic. using a gradient of 0-100% СΗ ₂ С1 ₂ / (СΗ ₂ С1 ₂ / МеОΗ / NΗ ₄ ОΗ) (90: 10: 1). The free base of the target compound was isolated in the form of a yellow solid (0.027 g).

M8 (E8 +) t / ζ 480.1 (MH ⁺ ).

'H NMR (400 MHz. Chloroform-ά) ppm 1.62 (d.1 = 2.53 Hz. 1H). 1.61 (broad s. 1H). 1.90-2.09 (m. 3H). 2.20-2.42 (m, 2H). 2.59-2.78 (m, 2H). 3.14 (dd. 1 = 12.88 Hz. 3.03 Hz. 2H). 3.53 (s. 2H). 4.05-4.14 (m, 2H). 4.41 (dd. 1 = 12.38 Hz. 9.35 Hz. 1H). 4.57 (dd. 1 = 12.63 Hz. 4.04 Hz. 1H). 5.04 (dd. 1 = 7.96 Hz. 4.42 Hz. 1H). 5.32 (s. 1H). 6.28 (dd. 1 = 16.29 Hz. 9.22 Hz. 2H). 7.49 (d. 1 = 3.28 Hz. 1H). 7.50-7.57 (m, 1H).

The target di-соль salt was obtained. dissolving the free base in SChCH1 ₂ and adding 0.113 ml of a mixture of 1N. ΗΟ / ether.

Example 35. (1H) -1 - ({4 - [(1.2.3-Benzothiadiazol-5-ylmethyl) amino] - 1-piperidinyl} methyl) -1.2 dihydro-4H.9H-imidazo [1.2.3-y] -1.8-naphthyridine-4.9-dione hydrochloride 'Ν'

Suspension (1H) -1 - ({4 - [(1.2.3-benzothiadiazol-5-ylmethyl) amino] -1-piperidinyl} methyl) -1.2 dihydro-4H.9H-imidazo [1.2.3-y] -1.8 -naphthyridine-4.9-dione dihydrochloride (for the preparation, see example 5Α (])) (60 mg. 0.161 mmol) in chloroform (2 ml) and methanol (0.100 ml) at ambient temperature under nitrogen atmosphere was treated with triethylamine (0.067 ml 0.482 mmol) and stirred at ambient temperature for 15 hours. The solution was then treated with 1.2.3-benzothiadiazole-5 carbaldehyde (for synthesis, see XVO 0208224. Example 20 (a)) (23.75 mg. 0.145 mmol) and stirred another 30 minutes The solution was then treated with sodium triacetoxyborohydride (102 mg. 0.482 mmol) and stirred at ambient temperature for 45 minutes. after 45 min, bCM8 showed completion of the reaction. Then, the reaction mixture was treated with a saturated aqueous solution of NaΗCO3 (10 ml) and extracted with 20% methanol / OCM (3 × 25 ml). The combined organic extracts were dried (MD8O ₄ ). filtered. evaporated and chromatographed (0-5% methanol / OCM 5% methanol / ESM). obtaining the free base of the target compound (26 mg. 36%) in the form of a light yellow solid.

Ή NMR (СОС1 _3. 400 MHz) δ 1.30-1.49 (m 2Н). 1.80-1.98 (m, 2H). 2.21-2.39 (m, 2H). 2.51-2.61 (m. 1H).

2.61-2.75 (m, 2H). 2.90-3.02 (m, 1H). 3.05-3.19 (m. 1H). 4.04 (p. 2H). 4.31-4.42 (m, 1H). 4.51-4.61 (m, 1H). 4.92-5.05 (m, 1H). 6.20-6.31 (m, 2H). 7.45-7.53 (2H. M). 7.71 (d. 1H). 8.11 (d. 1H). 8.56 (s. 1H).

M8 (E8 +) t / ζ 449 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of ESM. treated with 1 equiv. 1 M ΗΟ in diethyl ether and then evaporated. obtaining the target compound in the form of a mono--salt (16.2 mg. 20.8%).

Bc-m8. corresponding to the product.

Example 36. (1H) -1 - ({4 - [(2.3-Dihydro-1-benzofuran-5-ylmethyl) amino] -1-piperidinyl} methyl) -1.2 dihydro-4H.9H-imidazo [1.2.3- ϊ]] - 1.8-naphthyridine-4.9-dione hydrochloride

Suspension (1H) -1 - ({4 - [(1.2.3-benzothiadiazol-5-ylmethyl) amino] -1-piperidinyl} methyl) -1.2 dihydro-4H.9H-imidazo [1.2.3-y] -1.8 naphthyridine-4.9-dione dihydrochloride (for the preparation, see example 5Α (])) (60 mg. 0.161 mmol) in chloroform (2 ml) and methanol (0.100 ml) at ambient temperature under nitrogen atmosphere. treated with triethylamine (0.067 ml. 0.482 mmol) and stirred at ambient temperature for 15 minutes. The solution was then treated with 2.3-dihydro-1-benzofuran-5-carbaldehyde (commercially available) (0.020 ml. 0.161 mmol) and stirred for another 30 minutes. The solution was then treated with sodium triacetoxyborohydride (102 mg. 0.482 mmol) and stirred at ambient temperature for 45 minutes. Then it was treated with a saturated aqueous solution of NaΗCO3 (10 ml) and extracted with 20% methanol / ESM (3 × 25 ml). The combined organic fractions were dried (No. 18O ₄ ). filtered. evaporated and chromatographed (5-25%

- 54 015821 methanol / BSM), obtaining the free base of the target compound (24 mg, 34.5%) in the form of a white solid.

Ή NMR (SBS1 ₃ , 400 MHz) δ 1.22-1.49 (m, 2H), 1.79-2.10 (m, 2H), 2.21-2.40 (m, 2H), 2 45-2.58 (m, 1H),

2.61-2.72 (m, 2H), 2.90-3.01 (m, 1H), 3.05-3.15 (m, 1H), 3.21 (t, 2H), 3, 72 (s, 2H), 4.32-4.42 (m, 1H), 4.51-4.62 (m, 3H), 4.95-5.05 (m, 1H), 6.22- 6.33 (m, 2H), 6.72 (d, 1H), 7.14 (d, 1H), 7.19 (s, 1H), 7.45-7.52 (2H, m),

M8 (E8 +) t / ζ 433 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of BSM, treated with 1 equiv. 1 M HCl in diethyl ether and then evaporated to give the title compound in the form of a mono-HCl salt (22.7 mg, 28.6%).

Bc-m8 corresponding to the product.

Example 37. (1K) -1 - ({4 - [(3,4-Dihydro-2H-pyrano [2,3-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 -dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Suspension (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione dihydrochloride (for preparation see example 13 (k) or 15 (b)) (50 mg, 0.100 mmol) in chloroform (4 ml) and methanol (0.200 ml) at ambient temperature under nitrogen atmosphere was treated triethylamine (0.042 ml, 0.301 mmol) and stirred for 0.25 h (the suspension turned into a solution). Then 3,4-dihydro-2H-pyrano [2,3-c] pyridin-6-carbaldehyde was added (for synthesis see No. 2004058144, example 126 (e)) (16.35 mg, 0.100 mmol) and the reaction the mixture was stirred at ambient temperature for 0.5 hours. Sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was then added and the reaction mixture was stirred at ambient temperature. After 3 hours, there was still some starting material, so 30 mg of sodium triacetoxyborohydride was added. After 1 h, a saturated aqueous sodium bicarbonate solution (25 ml) was added, then 20% methanol / OCM (25 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted twice with 20% methanol / BSM (2x25 ml). The combined organic layers were dried on sodium sulfate, filtered and evaporated, yielding 60 mg of crude product. The crude product was purified by silica gel chromatography (0-20% MeOH / BSM) to give the free base of the target compound in the form of a yellow solid (39 mg, 87%).

Ή NMR (SBS1 ₃ , 400 MHz) δ 1.25-1.45 (m, 2H), 1.78-2.08 (m, 4H), 2.22-2.38 (m, 2H), 2 45-2.60 (m, 1H),

2.62 (d, 1H), 2.67-2.80 (m, 3H), 2.93 (d, 1H), 3.05-3.14 (m, 1H), 3.78 (s, 2H), 4.15-4.25 (m, 2H), 4.30-4.45 (m,

1H), 4.50-4.60 (m, 1H), 4.95-5.05 (m, 1H), 6.33 (d, 1H), 6.96 (s, 1H), 7.75 (s, 1H), 7.87 (s, 1H), 8.07 (s, 1H). M8 (E8 +) t / ζ 449 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of methanol / BSM mixture and treated with 1 equiv. 1 M hydrochloric acid in diethyl ether. The solvents were removed and the solid was dried in a desiccator (in the presence of P2O5) over the weekend to give the title compound in the form of a mono-HCl salt in the form of a yellow solid (40.6 mg, 79%).

Bcm8 was consistent with the product.

Example 38. (1K) -1 - ({4 - [(2,3-Dihydrofuro [2,3-c] pyridin-5-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione hydrochloride oSuspension (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro 3H, 8H-2a, 5.8a-triazacenaphthylene-

3,8-dione dihydrochloride (for preparation see example 13 (k) or 15 (b)) (50 mg, 0.100 mmol) in chloroform (20 ml) and methanol (0.800 ml) at ambient temperature under nitrogen atmosphere was treated triethylamine (0.042 ml, 0.301 mmol) and stirred for 0.25 h (the suspension turned into a solution). Then 2,3-dihydrofuro [2,3-c] pyridin-5-carbaldehyde was added (for synthesis see \ UO 2007122258, example 43 (ί) (14.94 mg, 0.100 mmol) and the reaction mixture was stirred at ambient temperature medium for 0.5 h. Then sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was added and the reaction mixture was stirred at ambient temperature. After 3 hours, some starting material still remained, so 30 mg of sodium triacetoxyborohydride was added. h was added a saturated aqueous solution of sodium bicarbonate (25 ml), then 20% methanol / CM (25 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted twice with 20% methanol / BSM (2x25 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to give 50 mg of crude product.

- 55 015821

The crude product was purified by silica gel chromatography (0-20% methanol / ΟΟΜ). obtaining the free base of the target compound in the form of a yellow solid (31 mg, 71.2%).

Ή NMR (SBS1 ₃ , 250 MHz) δ 1.25-1.43 (m, 2H), 1.81-2.00 (m, 2H), 2.22-2.35 (m, 2H), 2 , 49-2.54 (m, 1H), 2.66 (d, 1H), 2.71-2.74 (m, 1H), 2.92 (d, 1H), 3.07-3.12 (m, 1H), 3.19-3.24 (m, 2H), 3.82 (s, 2H), 4.37-4.42 (m, 1H), 4.56-4.62 (m , 3H), 4.96-5.06 (m, 1H), 6.33 (d, 1H), 7.18 (s, 1H), 7.76 (d, 1H), 7.86 (s, 1H), 8.06 (s, 1H).

Μ8 (E8 +) t / ζ 435 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of methanol / ΟΟ'Μ mixture and treated with 1 equiv. 1 M hydrochloric acid in diethyl ether. The solvents were removed and the solid was dried in a desiccator (in the presence of P2O5) over the weekend to give the title compound as a mono-HC1 salt in the form of an orange solid (33.5 mg, 67.4%).

ΓΟΜ8 matched the product.

Example 39. (2K) -2 - ({4 - [(3,4-Dihydro-2H-pyrano [2,3-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 -dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Suspension (2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione (for the preparation see Example 16A (])) (60 mg, 0.199 mmol) and 3,4-dihydro-2H-pyrano [2,3c] pyridine-6-carbaldehyde (for the synthesis, see AO 2004058144, Example 126 (e)) (29.2 mg, 0.179 mmol) in chloroform (2 ml) and methanol (0.061 ml) at ambient temperature under nitrogen atmosphere were treated with sodium triacetoxyborohydride (127 mg, 0.597 mmol) and stirred at ambient temperature for 30 min. The reaction mixture was then treated with saturated aqueous solution No. ₁ HCO ₃ (10 ml) and was extracted with a mixture of 20% methanol / CΜ (3x20 ml). The combined organic extracts were dried (Μ§8Ο ₄ ), filtered, evaporated and purified by silica gel chromatography using (0-20% Μ ^ Μ / ΩΟΜ ^ to give the free base of the target compound in the form of a light brown solid

Ή NMR (SBS1 ₃ , 400 MHz) δ 1.28-1.40 (m, 2H), 1.78-1.86 (m, 2H), 1.96-2.01 (m, 2H), 2 14-2.34 (m, 2H), 2.45-2.52 (m, 1H), 2.62-2.74 (m, 4H), 2.91 (m, 1H), 3.07 -3.11 (m, 1H), 3.74 (s, 2H), 4.16-4.18 (m, 2H), 4.32-4.37 (m, 1H), 4.48-4 52 (m, 1H), 4.97-5.03 (m, 1H), 6.34 (d, 1H), 6.93 (s, 1H), 7.72 (d, 1H), 7, 77 (s, 1H); 8.03 (s, 1H).

Μ8 (E8 +) t / ζ 449 (MH ⁺ ).

The free base of the target compound in a small amount of ΩΟΜ was treated with 1 equiv. 1 M HCl in diethyl ether (0.17 ml) was evaporated and dried in a desiccator overnight to give the title compound as a mono-HCl salt (57.3 mg, 56.4% yield).

Bc-Μδ corresponding to the product.

Example 40. (2K) -2 - ({4 - [(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl) amino] - 1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Suspension (2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione (for preparation see Example 16A (])) (60 mg, 0.199 mmol) and

2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (commercially available) (29.4 mg, 0.179 mmol) in chloroform (2 ml) and methanol (0.100 ml) were treated with sodium triacetoxyborohydride at ambient temperature under nitrogen atmosphere (127 mg, 0.597 mmol) and stirred for 90 min, after 90 min ΓΟΜ8 showed the completeness of the reaction. The reaction mixture was treated with saturated aqueous solution No. 1H.'Oz (10 ml) and was extracted with 20% methanol / ^ CΜ (3x25 ml). The combined organic extracts were dried (Μ§8Ο ₄ ), filtered, evaporated and chromatographed (0-20% methanol / ^ CΜ) to give the free base of the target compound (46.8 mg, 58.4%) in the form of a yellow gum.

Ή NMR (СОС1 ₃ , 400 MHz) δ 1.20-1.41 (m, 2Н), 1.73-1.91 (m, 2Н), 2.09-2.38 (m, 2Н), 2 42-2.55 (m, 1H),

2.61-2.72 (m, 2H), 2.85-2.95 (m, 1H), 3.05-3.15 (m, 1H), 3.68 (s, 2H), 4, 32 (m, 4H), 4.32-4.42 (m, 1H), 4.49-4.59 (m, 1H), 4.95-5.06 (m, 1H), 6.39 ( d, 1H), 6.71-6.85 (m, 3H), 7.75 (d, 1H), 7.81 (s, 1H).

Μ8 (E8 +) t / ζ 450 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of ΩΟ'Μ, treated with 1 equiv. 1 M HCl in diethyl ether and then evaporated to give the title compound as a mono-HCl salt (43.8 mg, 53.4%).

- 56 015821

Bc-m8 corresponding to the product.

Example 41. (2K) -2 - [(4 - {[(8-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1 piperidinyl) methyl] -1,2- dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Suspension (2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione (for the preparation see Example 16A (])) (58.5 mg, 0.194 mmol) and 8-fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (for the synthesis, see VO 2007122258, example 8 (b)) (31.8 mg, 0.175 mmol) in chloroform (2 ml) and methanol (0.100 ml) at ambient temperature under nitrogen atmosphere was stirred for 0.5 h. Then it was treated with sodium triacetoxyborohydride (123 mg, 0.582 mmol) and stirred for 90 minutes. Then it was treated with saturated aqueous solution No. HCO ₃ (10 ml) and was extracted with 20% methanol / ESM (3x25 ml). The combined organic extracts were dried (Ia ₈ O ₄ ), filtered, evaporated and purified by silica gel chromatography using (0-20% methanol / IMS) to obtain the yellow base free base of the target compound (44.9 mg, 49.5%).

Ή NMR (SIS1 ₃ , 400 MHz) δ 1.24-1.55 (m, 2H), 1.78-1.85 (m, 2H), 2.21-2.36 (m, 2H), 2 , 44-2.51 (m, 1H), 2.64-2.73 (m, 2H), 2.92 (d, 1H), 3.10-3.14 (m, 1H), 3.65 (s, 2H), 4.26-4.30 (m, 4H), 4.35-4.40 (m, 1H), 4.52-4.56 (m, 1H), 4.99-5 05 (m, 1H), 6.38 (d, 1H), 6.62-6.67 (m, 2H), 7.76 (d, 1H), 7.81 (s, 1H).

M8 (E8 +) t / ζ 468 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of ISM, treated with 1 equiv. 1 M HCl in diethyl ether and then evaporated and dried in a desiccator overnight to afford the title compound as a mono-HCl salt (30.1 mg, 29.2%).

Bc-m8 corresponding to the product.

Example 42. 7- {[(1- {[(2K) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-2-yl] methyl} -4 piperidinyl) amino ] methyl} -2,3-dihydro-1,4-benzodioxin-5-carbonitrile hydrochloride

Suspension (2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione (for the preparation see Example 16A (])) (60 mg, 0.199 mmol) and 7-formyl-2,3-dihydro-1,4-benzodioxin-5-carbonitrile (for the synthesis, see VO 06014580 , production example 13 or VO 2007122258, example 31 (f) (37.7 mg, 0.199 mmol) in chloroform (2 ml) and methanol (0.100 ml) at ambient temperature under nitrogen atmosphere was treated with sodium triacetoxyborohydride (127 mg, 0.597 mmol) ) and stirred for 90 minutes. it was then treated with saturated aqueous NaΗSOz (10 mL) and extracted with 20% methanol / IMS (3x25 mL). The combined organic extracts were dried (№8O ₄₎ fil Trovan, evaporated and purified by silica gel chromatography using (0-20% methanol / SEM) to give the free base of the title compound in the form of a yellow gum (40 mg, 42.3%).

Ή NMR (SIS1 ₃ , 400 MHz) δ 1.24-156 (m, 2H), 1.79-1.86 (m, 2H), 2.21-2.36 (m, 2H), 2.43 2.50 (m, 1H), 2.65-2.72 (m, 2H), 2.93 (d, 1H), 3.12-3.16 (m, 1H), 3.68 (s , 2H), 4.29-4.41 (m, 5H), 4.53-4.57 (m, 1H), 5.00-5.06 (m, 1H), 6.39 (d, 1H) ), 7.06-7.09 (m, 2H), 7.77 (d, 1H), 7.83 (s, 1H).

M8 (E8 +) t / ζ 475 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of ISM, treated with 1 equiv. 1 M HCl in diethyl ether, was evaporated and dried in an desiccator overnight to give the title compound as a mono-HCl salt (45 mg, 42%) as a light yellow solid.

Bc-m8 corresponding to the product.

Example 43. (2K) -2 - ({4 - [(2,3-Dihydrofuro [2,3-c] pyridin-5-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Suspension (2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione (for preparation see Example 16A (])) (70 mg, 0.232 mmol) and 2,3-dihydrofuro [2,3-57 015821

c] pyridine-5-carbaldehyde (for synthesis see ^ No. O 2007122258, example 43 (ί) (34.6 mg, 0.232 mmol) in chloroform (5 ml) and methanol (0.250 ml) at ambient temperature in the atmosphere nitrogen was stirred for 0.5 h (the suspension turned into a solution). Then sodium triacetoxyborohydride (155 mg, 0.697 mmol) was added and the reaction mixture was stirred at ambient temperature. After 3 h, no starting material remained, so a saturated aqueous bicarbonate solution was added. sodium (25 ml), then 20% methanol / OSM (25 ml) and an aqueous layer of extract and then separated from the organic layer. The aqueous layer was extracted twice with 20% methanol / OCM (2x25 ml). The combined organic extracts were dried on sodium sulfate, filtered and evaporated to give 90 mg of crude product. The crude product was purified by silica gel chromatography (0-20 % MeOH / OSM), obtaining the free base of the target compound in the form of a light yellow solid (77 mg, 76%).

Ή NMR (SBS1 ₃ , 400 MHz) δ 1.28-1.48 (m, 2H), 1.81-1.89 (m, 2H), 2.21-2.36 (m, 2H), 2 , 43-2.55 (m, 1H), 2.64-2.72 (m, 2H), 2.93 (d, 1H), 3.10-3.14 (m, 1H), 3.19 -3.23 (m, 2H), 3.81 (s, 2H), 4.34-4.40 (m, 1H), 4.52-4.61 (m, 3H), 4.95-5 08 (m, 1H), 6.37 (d, 1H), 7.17 (s, 1H), 7.76 (d, 1H), 7.81 (s, 1H), 8.06 (s, 1H).

M8 (E8 +) t / ζ 435 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of methanol / OSM mixture and treated with 1 equiv. 1 M hydrochloric acid in diethyl ether. The solvents were removed and the solid was dried in a desiccator (in the presence of P ₂ O ₅ ) over the weekend to give the title compound as a mono-HCl salt in the form of an off-white solid (78.9 mg, 68.5%).

Bcm8 was consistent with the product.

Example 44. (1K) -1 - ({4 - [(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl) amino] -1-piperidinyl} methyl) -

1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Suspension (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione dihydrochloride (for preparation see example 13 (k) or 15 (ά)) (50 mg, 0.100 mmol) in chloroform (4 ml) and methanol (0.200 ml) at ambient temperature under nitrogen atmosphere was treated triethylamine (0.042 ml, 0.301 mmol) and stirred for 0.25 h (the suspension turned into a solution). Then, 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (commercially available) (16.45 mg, 0.100 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 hours. Then sodium triacetoxyborohydride ( 67.1 mg, 0.301 mmol) and the reaction mixture was stirred at ambient temperature. After 3 hours, another 40 mg of sodium triacetoxyborohydride was added. After 1 h, another 30 mg of sodium triacetoxyborohydride was added. After 1 h, a saturated NaHCO3 solution (25 ml) was added, then 20% MeOH / OCM (25 ml) and the aqueous layer was separated from the organic layer. The aqueous layer was extracted twice with 20% MeOH / OCM (2x25 ml). The combined organic extracts were dried # 18O ₊ filtered and evaporated to give a crude product. The crude product was purified by silica gel chromatography (0-20% MeOH / OCM) to obtain 27 mg of the free base of the target compound (complete yield 59.9%).

Ή NMR (СОС1 ₃ , 400 MHz) δ 1.21-1.42 (m, 2Н), 1.70-1.92 (m, 2Н), 2.21-2.36 (m, 2Н), 2 , 41-2.55 (m, 1H), 2.58-2.78 (m, 2H), 2.88-2.98 (m, 1H), 3.05-3.14 (m, 1H) 3.68 (s, 2H), 4.25 (s, 4H), 4.43-4.52 (m, 1H), 4.51-4.62 (m, 1H), 4.98-5 06 (m, 1H), 6.34 (d, 1H), 6.75-6.84 (m, 3H), 7.76 (d, 1H), 7.87 (s, 1H).

M8 (E8 +) t / ζ 450 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of MeOH / OCM and treated with 1 equiv. a solution of 1 M HC1 in EO. The solvents were removed and the solid was dried in a desiccator (P2O5) overnight to give the title compound as a mono-HCl salt (26 mg, 0.051 mmol, 50.7% yield) as a yellow solid.

Example 45. (1K) -1 - ({4 - [([1,2,5] Thiadiazolo [3,4-b] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2- dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

- 58 015821

K (1H) -1 - [(4-amino-1-piperidinyl} methyl) -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-

Chloroform (3 ml), methanol (0.3 ml) and triethylamine (0.067 ml, 0.482 mmol) were added to the 4,9-dione dihydrochloride (for preparation see Example 5A (|) (60 mg, 0.161 mmol). stirred under nitrogen for 30 min, then [1,2,5] thiadiazolo [3,4-b] pyridin-6 carbaldehyde was added (for preparation see Example 49 (b)) (25.2 mg, 0.153 mmol) The reaction mixture was stirred for another 2 hours, then sodium triacetoxyborohydride (102 mg, 0.482 mmol) was added and stirring was continued for 16 hours. An additional amount of sodium triacetoxyborohydride (102 mg, 0, 482 mmol) and stirred for 30 minutes, an additional amount of sodium triacetoxyborohydride (102 mg, 0.482 mmol) was added and stirring was continued for 2 hours. The reaction mixture was partitioned between saturated NaHCO3 and 20% MeOH in ESM. The aqueous layer was further extracted with 20% MeOH in the ESM and the combined organic extracts were passed through a hydrophobic frit and concentrated to obtain a reddish-brown solid (~ 65 mg). It was purified by silica gel chromatography eluting with 0-20% MeOH in PCM to give the free base of the target compound in the form of a light tan gum (18 mg).

Ή NMR (SRzOR, 400 MHz) δ 1.30 (m, 1H), 1.42 (m, 1H), 1.88 (d broad, 1H), 1.98 (d broad, 1H), 2 28 (q, 2H), 2.63 (m, 2H), 2.89 (dd, 1H), 3.01 (dd, 1H), 3.06 (d broad, 1H), 4.08 (s, 2H), 4.45 (m, 2H), 5.10 (m, 1H), 6.28 (dd, 2H), 7.76 (d, 2H), 8.41 (d broad, 1H), 9.08 (d broad, 1H).

M8 (E8 +) t / ζ 450 (MH ⁺ ).

The free base of the target compound was dissolved in 2: 1 PCM: MeOH (1 ml) and HC1 (1 M in diethyl ether) (0.040 ml, 0.04 mmol) was added. The solvent was evaporated to give a light brown solid (22 mg, 28%).

Example 46 (1H) -1 - [(4 - {[(4-Fluoro-1H-benzimidazol-2-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-4H, 9H-imidazo [1 , 2,3-y] - 1,8-naphthyridine-4,9-didion hydrochloride

(1H) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine was added to a 10 ml round bottom flask -4,9-dione (for the preparation see Example 5A (])) (80 mg, 0.238 mmol), 4-fluoro-1H-benzimidazole-2-carbaldehyde (for the synthesis, see \ O 2003087098, example 320) (42.9 mg, 0.261 mmol) and sodium bicarbonate (100 mg, 1.190 mmol) in an ESM (4 ml) and methanol (1 ml) to obtain a brown suspension. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. After 15 hours, sodium triacetoxyborohydride (101 mg, 0.475 mmol) was added and the reaction mixture was stirred at 25 ° C. under nitrogen for 4 hours. The reaction mixture was adsorbed onto silica gel and purified using 0-10% MeOH / OCM (1% NH ₄ OH), obtaining the free base of the target compound.

LBM8 and ¹ H NMR were consistent with the desired product.

Ή NMR (Ό-4 MeOH, 400 MHz) δ 1.35-1.55 (m, 2H), 1.90-1.96 (m, 2H), 2.30-2.41 (m, 2H) 2.71-2.81 (m, 2H), 2.91-2.99 (m, 1H), 3.05-3.15 (m, 2H), 4.20 (s, 2H), 4 41-4.50 (m, 2H), 4.69 (s, 2H), 5.10-5.20 (m, 1H), 6.25

6.36 (m, 2H), 6.91-7.05 (m, 1H), 7.16-7.25 (m, 1H), 7.31-7.39 (m, 1H), 7, 75-7.81 (m, 2H).

M8 (E8 +) t / ζ 449 (MH ⁺ ).

The free base of the target compound was suspended in 10% MeOH / OCM and treated with 1N. HC1, obtaining the target compound as a salt of di-HC1 (17 mg, 0.033 mmol, yield 13.73%).

Example 47. (1H) -1 - [((28) -2 - {[([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] methyl} -4morpholinyl) methyl] -1 , 2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione dihydrochloride

(a) 1,1-Dimethylethyl [((28) -4 - {[(2H) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3- y] -1.8 naphthyridin-2-yl] methyl} -2-morpholinyl) methyl] carbamate.

(18) -1- (hydroxymethyl) -1,2,5,6-tetrahydro-4H, 9Nimidazo [1,2,3-y] -1,8-naphthyridine-4,9- was charged into a 100 ml round bottom flask dione (for preparation see Example 5A (e)) (450 mg, 2.043 mmol) and triethylamine (0.342 ml, 2.452 mmol) in an ESM (20 ml) at 0 ° C. to give an orange solution. Methanesulfonyl chloride (0.174 ml, 2.248 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. LMS8 showed that methane was formed

- 59 015821 sulfonate. The reaction mixture was diluted with ISM (100 ml) and washed with 2x25 ml of a saturated aqueous NaHCO3 solution. The organic phase was separated and dried over No. ₂ 8O _4. The solution was concentrated in vacuo and suspended in acetonitrile (20.00 ml). Pyridine (0.500 ml) was added, followed by 1,1-dimethylethyl [(2K) -2-morpholinyl methyl] carbamate (for synthesis see VO 2008009700, example 89 (e)) (884 mg, 4.09 mmol) and the reaction mixture heated at 75 ° C. The reaction mixture was stirred for 5 hours, after which LCM8 showed completion of the reaction. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The reaction mixture was diluted with ISM (100 ml) and washed with 25 ml of a saturated aqueous NaHCO3 solution. The organic phase was separated and dried over No. ₂ 8O ₄ , the Residue obtained was purified on silica gel, 0-10% MeOH / ISM, and the target compound (805 mg, 1.539 mmol, 75% yield) was isolated in the form of a red oil.

M8 (E8 +) t / ζ 419 (MH ⁺ ).

(b) 1,1-Dimethylethyl [((28) -4 - {[(1K) -4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1 , 8naphthyridin-1-yl] methyl} -2-morpholinyl) methyl] carbamate.

To a 50 ml round bottom flask was added 1,1-dimethylethyl [((28) -4 - {[(2K) -4,9-dioxo-1,2,8,9 tetrahydro-4H, 7H-imidazo [1,2, 3-y] -1,8-naphthyridin-2-yl] methyl} -2-morpholinyl) methyl] carbamate (805 mg, 1.924 mmol) in 1,4-dioxane (10 ml) at ambient temperature under nitrogen, getting an orange solution. ΌΌφ (655 mg, 2.89 mmol) was added and the reaction mixture became very dark. The reaction mixture was heated to 90 ° C in an oil bath and stirred for 30 minutes. The reaction mixture was cooled to ambient temperature, 200 ml of a 5% aqueous solution of K ₂ CO _{3 was} added, and the reaction mixture was extracted with ISM (3x200 ml). The combined organic layers were washed with saturated aqueous solution No. C1; the organic layer was separated and dried over No. 8O ₄ and concentrated to give a crude product. The crude product was added to a silica gel column and eluted with 0-20% MeOH / CHC1 ₃ to give the title compound (830 mg, 1.794 mmol, 93% yield) as a red oil.

M8 (E8 +) t / ζ 417 (MH ⁺ ).

(c) (1K) -1 - {[(28) -2- (Aminomethyl) -4-morpholinyl] methyl} -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1 8-naphthyridine-4,9-dione (HC1).

1,1-dimethylethyl [((28) -4 - {[(1K) -4,9-dioxo-1,2-dihydro4H, 9H-imidazo [1,2,3-y] was added to a 50 ml round bottom flask - 1,8-naphthyridin-1-yl] methyl} -2-morpholinyl) methyl] carbamate (830 mg,

1.993 mmol) in ISM (10 ml) to give a brown solution. 4n was added. HCl in dioxane (2.491 ml, 9.96 mmol) and the reaction mixture was stirred at ambient temperature. After 30 minutes, the solution became cloudy, so 2 ml of methanol was added and the reaction mixture was stirred for another 30 minutes. The reaction mixture was concentrated in vacuo to give the desired product as the HC1 salt (520 mg, 1.474 mmol, 74.0% yield) in the form of a brown solid, which was used without further purification.

(ά) Target connection.

(1K) -1 - {[((28) -2- (aminomethyl) -4-morpholinyl] methyl} -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] was added to a 10 ml round bottom flask -1,8-naphthyridine-4,9-dione (HC1) (85 mg, 0.241 mmol), [1,3] oxathiolo [5,4s] pyridin-6-carbaldehyde (40.3 mg, 0.241 mmol) (in for the synthesis see VO 2004058144, Example 61) and NaHCO ₃ (60.7 mg, 0.723 mmol) in ISM (4 ml) and methanol (1 ml) to obtain a yellow suspension. The reaction was stirred overnight and sodium triacetoxyborohydride (102 mg, 0.482 mmol) was added. The reaction mixture was stirred for 4 hours, then filtered through celite and the filter was washed with 10% MeOH / OCM. Silica gel chromatography eluting with 0-10% MeOH / CHC1 ₃ (1% IN ₄ OH) gave the free base of the target compound, in which L-M8, ¹ H NMR corresponded to the product.

Ή NMR (Ό-4 MeOH, 400 MHz) δ 2.02-2.13 (m, 1H), 2.34-2.49 (m, 2H), 2.60-2.78 (m, 2H) 2.85-3.08 (m, 2H), 3.40-3.68 (m, 2H), 3.72-3.89 (m, 1H), 4.40-4.51 (m, 2H), 4.89 (s, 2H), 5.10-5.20 (m, 1H), 5.80-5.89 (m, 2H), 6.23-6.38 (m, 2H) 7.72-7.82 (m, 2H); 7.90-7.96 (m, 2H).

M8 (E8 +) t / ζ 468 (MH ⁺ ).

The free base of the target compound was suspended in 10% MeOH / OCM and treated with 500 μl of 1N. HC1 in ether. The solution was concentrated in vacuo to afford the title compound as di-HCl salt (49 mg, 0.091 mmol, 37.6% yield) in the form of a tan solid.

- 60 015821

Example 48. (1K) -1 - {[(28) -2 - ({[(7-Chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6yl) methyl] amino} methyl) -4-morpholinyl] methyl} -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9dione dihydrochloride

(1K) -1 - {[((2K) -2- (aminomethyl) -4-morpholinyl] methyl} - was added to a 10 ml round bottom flask

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione (HCl) (for preparation see Example 47 (c)) (85 mg 0.241 mmol), 7-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde (51.0 mg, 0.241 mmol) (for synthesis see \ UO 2003064421, example 15 (c)) and NaHCO ₃ (60.7 mg, 0.723 mmol) in an ESM (4 ml) and methanol (1 ml) to give a yellow suspension. No. ₂ 8O ₄ (171 mg, 1.205 mmol) was added, the reaction mixture was stirred overnight, and sodium triacetoxyborohydride (102 mg, 0.482 mmol) was added. The reaction mixture was stirred for 4 hours, filtered through celite and the filter was washed with 10% MeOH / OCM. Silica gel chromatography eluting with 0-10% MeOH / CHC1 ₃ (1% MH ₄ OH) gave the free base of the target compound in which L-M8, ¹ H NMR corresponded to the desired product.

Ή NMR (Ό-4 MeOH, 400 MHz) δ 2.05-2.13 (m, 1H), 2.32-2.49 (m, 2H), 2.59-2.80 (m, 2H) , 2.88-3.07 (m, 3H), 3.42 (s, 2H), 3.40-3.49 (m, 1H), 3.58-3.67 (m, 1H), 3 72-3.96 (m, 3H), 4.42-4.51 (m, 2H), 4.68 (s, 2H), 5.105.18 (m, 1H), 6.22-6.35 (m, 2H), 7.39 (s, 1H), 7.72-7.80 (m, 2H).

M8 (E8 +) t / ζ 513/515 (MH ⁺ ).

The free base of the target compound was suspended in 10% MeOH / OCM and treated with 500 μl of 1N. HC1 in ether. The solution was concentrated in vacuo to afford the title compound as the di-HC1 salt (61 mg, 0.104 mmol, 43.2% yield) as a pale yellow solid.

Example 49. (2K) -2 - ({4 - [([1,2,5] Thiadiazolo [3,4-b] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2- dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione

(a) 6 - [(E) -2-Phenylethenyl] [1,2,5] thiadiazolo [3,4-b] pyridine.

To 6-bromo [1,2,5] thiadiazolo [3,4-b] pyridine (for the preparation, see Ιηάίηη 1oigia1 o1 CEetStu, 8ecEo B: Ogdashs SNetMgu 1ps1i01pd Meά ^ s ^ ua1 SNetMgu (1979), 17B (1 ), 13-16) (1.9 g, 8.79 mmol), [(E) -2-phenylethenyl] boronic acid (1.561 g, 10.55 mmol) and tetrakis-triphenylphosphine palladium (0) (0.508 g, 0.440 mmol) was added 1,4-dioxane (38 ml) and then potassium carbonate (1.276 g, 9.23 mmol) in water (19 ml). The reaction mixture was then stirred under reflux for 1.5 hours. The cooled reaction mixture was partitioned between chloroform and water. The phases were separated using a hydrophobic frit and the organic extracts concentrated to give a black solid / gum (~ 2.4 g). This crude material was purified by silica gel chromatography eluting with 20-50% ENAc in cyclohexane to give the product as a yellow / brown solid (0.88 g).

А NMR A-DMSO, 400 MHz) δ 7.36 (t, 1H), 7.45 (t, 2H), 7.55 (d, 1H), 7.70 (d, 2H), 7.78 ( d, 1H), 8.3 (s, 1H), 9.51 (s, 1H).

M8 (E8 +) t / ζ 240 (MH ⁺ ).

(b) [1,2,5] Thiadiazolo [3,4-b] pyridine-6-carbaldehyde.

To 6 - [(E) -2-phenylethenyl] [1,2,5] thiadiazolo [3,4-b] pyridine (0.88 g, 3.68 mmol) was added acetone (30 ml), methyl methyl morpholine-Choxide , 50 wt.% In water (1.525 ml, 7.35 mmol) and then osmium tetroxide in water (0.225 ml, 0.037 mmol). The reaction mixture was then stirred for 20 hours. Sodium periodate (3.15 g, 14.71 mmol) was added to the light brown solution, and stirring was continued for 45 minutes. The solvent was partially removed on a rotary evaporator and the residue was partitioned between chloroform and water. The aqueous layer was further extracted with chloroform, and the combined organic extracts were passed through a hydrophobic frit and concentrated to give a brown solid.

- 61 015821 nevo / black color (0,6 g). A portion of this material (0.575 g) was purified by silica gel chromatography eluting with 20% EuAc in cyclohexane to give a pale yellow solid (160 mg).

Ή NMR (B ₆ -DMSO, 400 MHz) δ 9.18 (s, 1H), 9.49 (s, 1H), 10.30 (s, 1H).

(c) Target compound.

K (2K) -2 - [(4-aminocyclohexyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione dihydrochloride (for the preparation, see example 16A (] )) (100 mg, 0.333 mmol) chloroform (3 ml), methanol (0.300 ml) and triethylamine (0.139 ml, 0.999 mmol) were added. The mixture was stirred for 20 minutes, then [1,2,5] thiadiazolo [3,4-b] pyridin-6-carbaldehyde (52.2 mg, 0.316 mmol) was added. The reaction mixture was stirred overnight, then sodium triacetoxyborohydride (212 mg, 0.999 mmol) was added and stirring was continued for 1 hour. Additional sodium triacetoxyborohydride (212 mg, 0.999 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was separated between sat. NaHCO ₃ and 20% MeOH in chloroform. The aqueous layer was further extracted with 20% MeOH in chloroform, and the combined organic extracts were passed through a hydrophobic frit and concentrated. This crude material (~ 110 mg) was purified by chromatography, eluting with 0-20% MeOH in an ESM. receiving the product (46 mg, 27%). It was freeze-dried from 1,4-dioxane to give the title compound as a light brown solid (45 mg, 25%).

Ή NMR (SPS1 ₃ , 400 MHz) δ 1.38 (m, 2H), 1.91 (t, 2H), 2.25 (dt, 1H), 2.35 (dt, 1H), 2.58 ( m, 1H), 2.71 (m, 2H), 2.96 (d broad, 1H), 3.16 (dd, 1H), 4.06 (s, 2H), 4.40 (dd, 1H ), 4.56 (dd, 1H), 5.04 (m, 1H), 6.40 (d, 1H), 7.78 (d, 1H), 7.83 (s, 1H), 8.26 (s, 1H).

(E8 +) t / ζ 451 (MH ⁺ ).

Example 50. (1K) -1 - ({4 - [(3,4-Dihydro-2H-chromen-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H, 9H-imidazo [1 , 2,3-y] - 1,8-naphthyridine-4,9-dione hydrochloride

Solution (1K) -1 - [(4-amino-1-piperidinyl) methyl] - 1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8 naphthyridine-4,9-dione dihydrochloride (for preparation see Example 5A (])) (188 mg, 0.503 mmol) and triethylamine (0.175 ml, 1.256 mmol) in chloroform (4.5 ml) and methanol (0.5 ml) were stirred at ambient temperature at ambient temperature for 15 minutes, then 3,4-dihydro-2H-chromene-7-carbaldehyde was added dropwise at ambient temperature (for synthesis see ^ O 2007067511, Example 19 (chroman-7-carbaldehyde)) (68 mg, 0.419 mmol) in chloroform (2 ml). The reaction mixture was stirred at ambient temperature for 1 h, then sodium triacetoxyborohydride (444 mg, 2.096 mmol) was added in one portion, and the reaction mixture was stirred at ambient temperature overnight. Bc-m8 showed a product mixture containing some residual aldehyde. Additional sodium triacetoxyborohydride (267 mg, 1.258 mmol) was added and the reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was quenched with NaHCO ₃ (aqueous solution) (20 ml) and extracted with 20% MeOH / OCM (3x30 ml). The combined organic layers were dried over MgSO ₄ , filtered, evaporated and chromatographed (0-50% MeOH / OCM) to give the free base of the target compound in the form of a light yellow clear oil (49 mg, 0.11 mmol, 26%).

Ή NMR (CBC1 ₃ , 400 MHz) δ 1.28-1.42 (m, 2H), 1.78-1.87 (m, 2H), 1.97-2.01 (m, 2H), 2 17-2.31 (m, 2H),

2.47-2.55 (m, 1H), 2.62-2.68 (m, 2H), 2.74-2.77 (m, 2H), 2.95 (d, 1H), 3.07 ( dd, 1H), 3.71 (m, 2H), 4.17 (t, 2H), 4.35 (dd, 1H), 4.56 (dd, 1H), 4.96-5.02 (m , 1H), 6.23-6.31 (m, 2H), 6.72 (s, 1H), 6.77 (dd, 1H), 6.98 (d, 1H),

7.47-7.50 (m, 2H).

(E8 +) t / ζ 447 (MH ⁺ ).

The free base of the target compound in 2 ml of ESM was treated with 1 equiv. 1 M HCl in diethyl ether and then evaporated to give the title compound as a mono-HCl salt in the form of a light orange powder (51 mg, 25%).

Bcm8 was consistent with the product.

Example 51. (1K) -1 - ({4 - [(2,3-Dihydro-1-benzofuran-6-ylmethyl) amino] - 1-piperidinyl} methyl) -1,2 dihydro-4H, 9H-imidazo [1 , 2,3-y] - 1,8-naphthyridine-4,9-dione hydrochloride

(a) 2,3-dihydro-1-benzofuran-6-carbaldehyde.

To a solution of 6-bromo-2,3-dihydro-1-benzofuran (190 mg, 0.955 mmol) in THE (4 ml) at -78 ° C was added i-Cu (1.313 ml, 2.100 mmol). The reaction mixture was stirred at -78 ° C for 45 minutes, then a solution of OME (1.109 ml, 1.6 M in hexanes, 14.32 mmol) in THE (2 ml) was added dropwise and the reaction

- 62 015821 The mixture was stirred at -78 ° C for 10 minutes, then heated to ambient temperature and stirred for 1 hour. LSM8 did not show the preservation of any starting material. The reaction mixture was stirred at ambient temperature for another 2.5 hours. The reaction mixture was carefully poured into 2 M HCl (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic extracts were washed with brine (50 mL), dried over Md8O _4, filtered, evaporated and chromatographed (eluting 0-100% E! OAc / hexane).

The appropriate fractions were combined and evaporated to give the product in the form of a clear, colorless oil (44 mg, 0.297 mmol, 31%).

Ή NMR (CBC1 ₃ , 400 MHz) δ 3.28 (t, 2H), 4.64 (t, 2H), 7.26 (s, 1H), 7.33-7.39 (m, 2H), 9.91 (s, 1H).

(B) Target compound.

A solution of (1B) -1 - [(4-amino-1-piperidinyl) methyl] - 1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8 naphthyridine-4,9-dione dihydrochloride (for preparation see Example 5A (])) (133 mg, 0.356 mmol) and triethylamine (0.124 ml, 0.891 mmol) in chloroform (4.5 ml) and methanol (0.5 ml) were stirred at ambient temperature at ambient temperature for 15 minutes, then 2,3-dihydro-1-benzofuran-6-carbaldehyde (44 mg, 0.297 mmol) in chloroform (2 ml) was added dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with NaHCO ₃ (aqueous solution) (20 ml), extracted with 20% MeOH / ESM (3x30 ml). The combined organic layers were dried over Md8O _4, filtered, evaporated and chromatographed (0-50% MeOH / OCM). The relevant fractions were combined and evaporated to give the free base of the target compound in the form of a light yellow clear oil (18 mg, 0.04 mmol, 26%).

Ή NMR (SPS1 ₃ , 400 MHz) δ 1.40-1.53 (m, 2H), 1.85-1.92 (m, 2H), 2.16-2.30 (m, 2H), 2 54-2.68 (m, 3H), 2.98 (d, 1H), 3.08 (dd, 1H), 3.16 (t, 2H), 3.78 (s, 2H), 4, 33-4.38 (m, 1H), 4.52-4.57 (m, 3H), 4.96-5.02 (m, 1H), 6.24 (d, 1H), 6.29 ( d, 1H), 6.79 (s, 1H), 6.84 (d, 1H), 7.13 (d, 1H), 7.47-7.50 (m, 2H).

M8 (E8 +) w / ζ 433 (MH ⁺ ).

The free base of the target compound in 2 ml of an ESM was treated dropwise with 1 M HC1 in diethyl ether (0.04 ml, 0.04 mmol) to obtain the target compound as a mono-HC1 salt in the form of an orange powder (20 mg, 14%).

Example 52. (1B) -1 - ({4 - [(3,4-Dihydro-2H-chromen-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H, 9H-imidazo [1 , 2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride

Solution (1B) -1 - [(4-amino-1-piperidinyl) methyl] - 1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8 naphthyridine-4,9-dione dihydrochloride (for preparation see Example 5A (])) (12 mg, 0.032 mmol) and triethylamine (0.139 ml, 0.999 mmol) in an ESM (4.5 ml) and methanol (0.5 ml) were stirred at ambient temperature within 5 minutes 3,4-Dihydro-2H-chromene-6-carbaldehyde (commercially available) (45 mg, 0.277 mmol) was added and the resulting solution was stirred overnight for 18 hours. LS-M8 showed that the aldehyde remained and no amine remained . Additional amount of (1B) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3y] -1,8-naphthyridine-4.9 was added dione (120 mg, 0.321 mmol) and an additional amount of triethylamine (0.138 ml, 0.999 mmol) and the resulting mixture was stirred for 1 hour. An additional amount of sodium triacetoxyborohydride (294 mg, 1.387 mmol) was added and the resulting solution was stirred for 60 hours. The reaction mixture was diluted with ESM (10 ml) and a solution (10 ml) of sodium bicarbonate and stirred at ambient temperature for 10 min and was extracted with a mixture of methane LUSM (20%, 3x150 ml). The combined organic extracts were dried (Md8O _4), filtered, evaporated and chromatographed (0-50% metanolYuSM). The column wastes were concentrated to give a brown oil, which was rechromatographed (0-50% methanol / L). The relevant fractions were combined to give the free base of the target compound in the form of a white solid (27 mg, 0.06 mmol, 22%).

Ή NMR (SPS1 ₃ , 400 MHz) δ 1.76-1.86 (m, 2H), 1.91-1.97 (m, 2H), 2.04-2.06 (mm, 2H), 2 15 (t, 1H), 2.24 (t, 1H), 2.62 (dd, 1H), 2.75-2.81 (m, 4H), 3.06-3.14 (m, 2H) ), 3.85 (s, 2H), 4.12 (t, 2H), 4.40 (dd, 1H), 4.51 (dd, 1H), 4.96-5.02 (m, 1H) 6.22-6.29 (m, 2H); 6.77 (d, 1H); 7.25-7.27 (m, 2H); 7.47-7.50 (m, 2H).

M8 (E8 +) w / ζ 447 (MH ⁺ ).

The free base of the target compound in chloroform (5 ml) and methanol (3 ml) was treated by adding dropwise hydrochloric acid in ether (1 M, 0.06 ml, 0.06 mmol) to obtain the target compound as a mono-HC1 salt in the form white solid (6 mg, 4%).

- 63 015821

Example 53. (2K) -2 - [(4 - {[(5-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1 piperidinyl) methyl] -1,2- dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

(a) 5-Fluoro-2,3-dihydro -1,4-benzodioxin.

A solution of 3-fluoro-1,2-benzenediol (5.278 g, 41.2 mmol) in OME (50 ml) was treated with potassium carbonate (17.08 g, 124 mmol) and 1,2-dibromethane (3.91 ml, 45 , 3 mmol) and stirred at ambient temperature for 72 hours. The reaction mixture was treated with water (200 ml) and extracted with 3x200 ml (EUAc). The combined organic extracts were washed with water (200 ml), brine (200 ml), dried (MdO ₄ ), evaporated and chromatographed (0-20% EJAc-cyclohexane) to give the product in the form of a clear oil (2.437 g, 38%).

'H NMR (SPS1 ₃ , 400 MHz) δ 4.22-4.39 (m, 4H), 6.60-6.82 (m, 3H).

(b) 6-Bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin.

A solution of 5-fluoro-2,3-dihydro-1,4-benzodioxin (0.335 g, 2.173 mmol) in methanol (10 ml) at 0 ° C was treated with bromine (0.134 ml, 2.61 mmol), allowed to warm to ambient temperature medium for 10 minutes and stirred at ambient temperature for 18 hours. The reaction mixture was then treated with saturated aqueous sodium metabisulfate solution (100 ml), extracted with 3x100 ml (OSM), the combined organic extracts were dried (MD8O ₄ ), filtered, evaporated, chromatographed (0-50% ENAc: cyclohexane) to give the product in the form of a clear oil, which atverdevalo in the freezer to give a white solid (351 mg, 59%).

'|| NMR (SBS1 ₃ , 400 MHz) δ 4.20-4.39 (m, 4H), 6.52-6.65 (m, 1H), 6.91-7.05 (m, 1H).

(c) 5-Fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde.

A solution of 6-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin (146 mg, 0.627 mmol) in THE (5 ml) was treated with i-VI (0.551 ml, 1.378 mmol) at -78 ° C in nitrogen atmosphere and stirred at -78 ° C for 15 min before treatment with a solution of OME (0.243 ml, 3.13 mmol) in THE (2.00 ml). The reaction mixture was stirred for 10 min at -78 ° C and then the reaction medium was allowed to warm to ambient temperature for 10 min and stirred at ambient temperature for 0.5 h. The reaction mixture was treated with 2 M HC1 (20 ml) and extracted with ethyl acetate (3x100 ml). The organic extracts were evaporated, dried (MD8O4), filtered, evaporated, chromatographed (0-100% EJAc: cyclohexane) to give the product in the form of a white solid (25 mg, 22%).

M8 (E8 +) t / ζ 183 (MH ⁺ ).

(ά) Target connection.

Suspension (2K) -2 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione dihydrochloride (for the preparation see Example 16A (]), the amine was converted to dihydrochloride after purification by chiral HPLC) (51.3 mg, 0.137 mmol) in chloroform (5 ml) and methanol (0.1 ml) at ambient temperature in argon atmosphere was treated with triethylamine (0.057 ml, 0.411 mmol) and stirred at ambient temperature for 0.25 hours. The solution was then treated with 5-fluoro-2,3-dihydro-1,4-benzodioxin-6- carbaldehyde (24.95 mg, 0.137 mmol) and stirred for another 0.5 hours. The solution was then treated with sodium triacetoxyborohydride (174 mg, 0.822 mmol) and stirred at ambient temperature for 2 h, added additional sodium triacetoxyborohydride (174 mg, 0.137 mmol) and the reaction mixture was stirred for another 1 hour, the reaction mixture was then treated with saturated aqueous NaHCO ₃ (20 mL) and extracted with 20% methanol / OSM (3x20 ml). The combined organic extracts were dried (Md8O ₄₎ and chromatographed (0-20% metanolYuSM) to give the free base of the title compound as a white solid (29 mg, 0.062 mmol, 45%).

'|| NMR (SPS1 ₃ , 400 MHz) δ 1.20-1.46 (m, 2H), 1.73-1.95 (m, 2H), 2.15-2.39 (m, 2H), 2, 41-2.55 (m, 1H), 2.61-2.75 (m, 2H), 2.88-3.00 (m, 1H), 3.10-3.20 (m, 1H), 3.78 (s, 2H); 4.22-4.42 (m, 5H). 4.51-4.60 (m, 1H), 4.95-5.09 (m, 1H), 6.38 (d, 1H), 6.62 (m, 1H), 6.71-6, 80 (m, 1H), 7.76 (d, 1H), 7.81 (s, 1H).

M8 (E8 +) t / ζ 468 (MH ⁺ ).

The free base of the target compound (29 mg) in ESM / MeOH 2: 1 (5 ml) was treated with 1 M HCl in diethyl ether (62 μl) and then evaporated to give the target compound as a mono-HCl salt (31 mg, 0.062 mmol) in the form of a yellow solid.

- 64 015821

Example 54. (1K) -1 - {[(28) -2 - ({[(7-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} methyl) -4morpholinyl] methyl} -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione dihydrochloride

(1K) -1 - {[((2K) -2- (aminomethyl) -4-morpholinyl] methyl} - was added to a 10 ml round bottom flask

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione (HC1) (85 mg, 0.241 mmol) (for preparation see Example 47 (c)), 7-fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (48.3 mg,

0.265 mmol) (for synthesis see \ UO 2002056882, example 23 (a)) and No. ₁ HCO ₃ (60.7 mg, 0.723 mmol) in an ESM (4 ml) and methanol (1 ml) to obtain a yellow suspension. Sodium sulfate (171 mg, 1.205 mmol) was added, the reaction mixture was stirred overnight, after which sodium triacetoxyborohydride (102 mg, 0.482 mmol) was added. The reaction mixture was stirred for 4 hours, after which LCM8 showed that the reaction was complete. The reaction mixture was diluted with 10% MeOH in ESM (20 ml), filtered, adsorbed onto silica gel and purified by silica gel chromatography eluting with 0-10% MeOH / CHC ₃ (1%% ^ ΘΕ) to obtain the free base of the target compound, in wherein bC-M8, ¹ H NMR corresponded to the desired product.

Ή NMR (Ό-4 MeOH, 400 MHz) δ 2.03-2.10 (m, 1H), 2.33-2.49 (m, 2H), 2.51-2.68 (m, 2H) 2.83-2.95 (m, 2H), 2.99-3.07 (m, 1H), 3.39 (s, 2H), 3.41-3.50 (m, 1H), 3 55-3.63 (m, 1H), 3.68-3.80 (m, 3H), 4.42-4.51 (m, 2H), 4.79 (s, 2H), 5.08 -5.18 (m, 1H), 6.22-6.32 (m, 2H), 6.58-6.62, (m, 1H), 6.81-6.88 (m, 1H), 7.73-7.80 (m, 2H).

M8 (E8 +) t / ζ 483 (MH ⁺ ).

The free base of the target compound was diluted in 5% MeOH / CHC1 ₃ and treated with 1N. HCl in ether 100 μl and concentrated, obtaining the target compound as a salt of di-HCl (55 mg, 0.099 mmol, yield 41.1%) in the form of a light yellow solid.

Example 55. (1K) -1 - [((38) -3 - {[([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] methyl} -1pyrrolidinyl) methyl] -1 , 2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione dihydrochloride

(a) 1,1 - Dimethylethyl- (3 8) -3- {[(trifluoroacetyl) amino] methyl} -1-pyrrolidinecarboxylate.

To a 100 ml round bottom flask was added 1,1-dimethylethyl- (38) -3- (aminomethyl) -1 pyrrolidine carboxylate (commercially available) (750 mg, 3.74 mmol) in (ESM) (20 ml) to give a colorless solution. Triethylamine (1.044 ml, 7.49 mmol) was added and the reaction mixture was cooled to 0 ° C. Trifluoroacetic anhydride (0.635 ml, 4.49 mmol) was added and the reaction mixture was allowed to warm to ambient temperature with stirring for 14 hours. The solution was diluted with 100 ml ESM and washed with a saturated aqueous NaHCO ₃ solution and saturated aqueous solution No. C1. The organic layer was separated, dried over No. ₂ 8O ₄ , filtered and concentrated. The residue was subjected to silica gel chromatography to give the product (0.990 g, 3.34 mmol, 89% yield) in the form of a light yellow oil.

M8 (E8 +) t / ζ 297 (MH ⁺ ).

(b) 2,2,2-Trifluoro-No. [(3K) -3-pyrrolidinylmethyl] acetamide hydrochloride.

To a 100 ml round bottom flask was added 1,1-dimethylethyl- (38) -3 - {[(trifluoroacetyl) amino] methyl} -1-pyrrolidinecarboxylate (830 mg, 2.80 mmol) in an ESM (25 ml) at 25 ° C, obtaining a colorless solution. 4n was added. HCl (3.50 ml, 14.01 mmol) in dioxane and the reaction mixture was stirred overnight. The reaction mixture was concentrated in vacuo to give the desired compound in the form of a colorless oil, which was used in the next reaction without further purification. Allocated

2,2,2-trifluoro-No. [(3K) -3-pyrrolidinylmethyl] acetamide (550 mg, 2.364 mmol, 84% yield).

M8 (E8 +) t / ζ 197 (MH ⁺ ).

(c) No. [((38) -1 - {[(2K) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1 , 8-naphthyridin-2yl] methyl} -3-pyrrolidinyl) methyl] - 2,2,2-trifluoroacetamide.

(18) -1- (hydroxymethyl) -1,2,5,6-tetrahydro4H, 9H ~ imidazo [1,2,3-y] -1,8-naphthyridine-4,9- was added to a 100 ml round bottom flask dione HC1 (for preparation see Example 47 (c)) (350 mg, 1.589 mmol), triethylamine (0.266 ml, 1.907 mmol) in an ESM (20 ml) at 0 ° C., giving an orange solution. Methanesulfonyl chloride (0.135 ml, 1.748 mmol) was added and the reaction mixture was allowed to

- 65 015821 to warm to ambient temperature and stirred for 1 hour. LSM8 showed that methanesulfonate was formed. The reaction mixture was diluted with ESM (100 ml) and washed with 2x25 ml of a saturated aqueous NaHC- ₃ solution. The organic phase was separated and dried over Νη ₂ 8Ο4. The solution was concentrated in vacuo, diluted with acetonitrile (20.00 ml) and pyridine (0.500 ml) was added. 2,2,2-trifluoro-No [(3K) -3-pyrrolidinylmethyl] acetamide (550 mg, 2.364 mmol) was added and the reaction mixture was heated to 80 ° C and stirred for 25 hours. LBCM8 showed completion of the reaction. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The reaction mixture was diluted with ESM (100 ml) and washed with 25 ml of a saturated NaHC- ₃ solution. The organic phase was separated and dried over ^^ Οψ. The crude product was purified on silica gel eluting with 0-15% HeΜH / ^ CΜ to give the product (240 mg, 0.602 mmol, 37.9% yield) in the form of a light yellow oil.

M8 (E8 +) t / ζ 399 (MH ⁺ ).

(ά) No. [((38) -1 - {[(1K) -4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine -1-yl] methyl} 3-pyrrolidinyl) methyl] -2,2,2-trifluoroacetamide.

In a round bottom flask of 25 ml at ambient temperature in a nitrogen atmosphere was added No. [((38) -1 - {[(2K) -4,9-dioxo-1,2,8,9-tetrahydro-4H, 7H-imidazo [1,2,3-y] -1,8-naphthyridin-2-yl] methyl} -3pyrrolidinyl) methyl] -2,2,2-trifluoroacetamide (240 mg, 0.602 mmol) in 1,4-dioxane (5 ml), getting an orange solution. EER (205 mg, 0.904 mmol) was added and the reaction mixture became very dark. The reaction mixture was heated to 80 ° C. in an oil bath and stirred for 10 hours. The reaction mixture was cooled to ambient temperature. A 5% aqueous solution of Κ ₂ ί.'Ο ₃ (20 ml) was added and the reaction mixture was extracted with ESM (3x100 ml). The combined organic layers were washed with a saturated aqueous №1S1 and the organic phase was dried over № ₂ 8Ο _4, filtered and concentrated to give the crude product. The crude product was added to a silica gel column and eluted with 020% ΜeΟN / CHC1 ₃ to give the product (85 mg, 0.214 mmol, yield 35.6%) in the form of an orange solid.

M8 (E8 +) t / ζ 397 (MH ⁺ ).

(f) (1K) -1 - {[(38) -3- (Aminomethyl) -1-pyrrolidinyl] methyl} -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1 8naphthyridine-4,9-dione.

No. [((38) -1 - {[(1K) -4,9-dioxo-1,2-dihydro-4H, 9 Nimidazo [1,2,3-y] - 1.8 was added to a 25 ml round bottom flask naphthyridin-1-yl] methyl} -3-pyrrolidinyl) methyl] -2,2,2-trifluoroacetamide (85 mg, 0.214 mmol) in methanol (9 ml) and water (1.00 ml) to give a yellow solution. Potassium carbonate (59.3 mg, 0.429 mmol) was added and the reaction mixture was stirred overnight. Bcm8 showed completion of the reaction. The reaction mixture was diluted with 20% HeΟH / ^ CΜ (100 ml), dried over Νη ₂ 8Ο4, filtered and concentrated to give the product (60 mg, 0.200 mmol, 93% yield) in the form of an orange solid.

M8 (E8 +) t / ζ 301 (MH ⁺ ).

(ί) Target connection.

(1K) -1 - {[((38) -3- (aminomethyl) -1-pyrrolidinyl] methyl} - was added to a 10 ml round bottom flask

1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione (60 mg, 0.200 mmol), [1,3] oxathiolo [5,4s ] pyridine-6-carbaldehyde (33.4 mg, 0.200 mmol) (for synthesis see νΟ2004058144, example 61) and sodium sulfate (250 mg, 1.760 mmol) in an ESM (4 ml) and methanol (1.00 ml ), obtaining an orange suspension. The reaction mixture was stirred overnight under nitrogen. Sodium triacetoxyborohydride (85 mg, 0.400 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with 10% HeΟH / ^ CΜ (20 ml), filtered, adsorbed onto silica gel and then purified by silica gel chromatography eluting with 0-10% elution. HeΟH / ^ CΜ (1% NH ₄ ΟH), obtaining the free base of the target compound in the form of a yellow oil. BCM8 / NMR was consistent with the desired product.

Ή NMR (Ό-4 MeOH, 400 MHz) δ 1.34-1.43 (m, 1H), 1.85-1.96 (m, 1H), 2.15-2.30 (m, 2H) 2.38-2.51 (m, 3H), 2.68-2.75 (m, 1H), 2.04-3.17 (m, 2H), 3.41-3.50 (m, 1H), 3.69 (s, 2H), 4.42-4.51 (m, 2H), 5.08-5.18 (m, 1H), 5.83 (s, 2H), 6.26 -6.32 (m, 2H), 7.33 (s, 1H), 7.73-7.78 (m, 2H), 7.94 (s, 1H).

M8 (E8 +) t / ζ 452 (MH ⁺ ).

The free base of the target compound was diluted with 10% HeΟH / CHC1 ₃ , 100 μl of 1N was added. HCl in ether and the mixture was concentrated in vacuo to afford the title compound as the dihydrochloride salt (47 mg, 0.090 mmol, 44.9% yield) in the form of a tan solid.

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Example 56. 7 - {[(1 - {[(1H) -3.8-dioxo-1.2-dihydro-3H.8H-2a.5.8a-triazacenaphthylene-1-yl] methyl} -4 piperidinyl) amino] methyl} -2.3 -dihydro-1.4-benzodioxin-5-carbonitrile hydrochloride

Suspension (1H) -1 - [(4-amino-1-piperidinyl) methyl] -1.2-dihydro-3H.8H-2a.5.8a-triazacenaphthylene-

3.8-dione dihydrochloride (for preparation see example 13 (k) or 15 (ά)) (50 mg. 0.100 mmol) in chloroform (4 ml) and methanol (0.121 ml) at ambient temperature under nitrogen atmosphere was treated with triethylamine ( 0.587 ml. 4.21 mmol) and stirred for 15 minutes (the suspension turned into a solution). Then 7-formyl-2.3-dihydro-1.4-benzodioxin-5-carbonitrile was added (for synthesis see νθ 06014580. Preparation Example 13 or νθ 2007122258. Example 31 (ά)) ((18.95 mg. 0.100 mmol) and the reaction mixture was stirred for 30 minutes, then sodium triacetoxyborohydride (63.7 mg. 0.301 mmol) was added and the reaction mixture was stirred for 1 h. After 1 h, LMC8 showed a certain amount of intermediate imine, so additional sodium triacetoxyborohydride (63.7 mg. 0.301 mmol) was added and the reaction mixture was stirred for 2 hours. After this time the LBM8 exchange still showed the presence of an intermediate imine. An additional amount of sodium triacetoxyborohydride (63.7 mg. 0.301 mmol) was added and the reaction mixture was stirred overnight (16 h). After this time, LBM8 did not show any starting material. A saturated Na NCO3 solution was added (10 ml), then 20% MeOCH / ESM (20 ml) and the aqueous phase was extracted and then separated from the organic layer. The aqueous phase was extracted again using 20% MeOCH / ESM (2 x 20 ml). The combined organic extracts were dried by ЩА8О ₄ ). filtered and evaporated. getting a raw product. The crude product was purified on a silica gel column (0-20% MeOI / ESM). getting the free base of the target compound (33 mg. 69.4%).

'H NMR (СОС1 _3. 400 MHz) δ 1.15-1.41 (m, 2Н). 1.72-1.91 (m, 2H). 2.19-2.39 (m, 2H). 2.40-2.52 (m, 1H). 2.53-2.78 (m, 2H). 2.89-2.98 (m, 1H). 3.02-3.14 (m. 1H). 3.68 (s. 2H). 4.22-4.49 (m, 5H). 4.51-4.62 (m, 1H). 4.98-5.08 (m, 1H). 6.32 (d. 1H). 7.06 (m. 2H). 7.78 (d. 1H). 7.88 (s. 1H).

M8 (E8 +) t / ζ 475 (MJ).

The free base of the target compound was dissolved in a small amount of ESM and treated with 1 equiv. 1 M ΗΟ in diethyl ether. This gave the title compound in the form of a mono Ηί'Ί salt (33 mg. 65%).

Example 57. (1H) -1 - [(4 - {[(7-Fluoro-2.3-dihydro-1.4-benzodioxin-6-yl) methyl] amino} -1 piperidinyl) methyl] -1.2-dihydro-3Η.8H- 2a.5.8a-triazacenaphthylene-3.8-dione hydrochloride

Suspension (1H) -1 - [(4-amino-1-piperidinyl) methyl] -1.2-dihydro-3H.8H-2a.5.8a-triazacenaphthylene-

3.8-dione dihydrochloride (for preparation see Example 13 (k)) or 15 (ά) (50 mg. 0.100 mmol) in chloroform (3 ml) and methanol (0.150 ml) at ambient temperature under nitrogen atmosphere was treated with triethylamine ( 0.042 ml. 0.301 mmol) and stirred for 0.25 h (the suspension turned into a solution). Then 7-fluoro-2.3-dihydro-1.4-benzodioxin-6-carbaldehyde was added (for synthesis see νθ 2002056882. Example 23 (a)) (18.25 mg. 0.100 mmol) and the reaction mixture was stirred at ambient temperature for 0.5 h. Then sodium triacetoxyborohydride (67.1 mg. 0.301 mmol) was added and the reaction mixture was stirred at ambient temperature. After 1 h, an additional amount of sodium triacetoxyborohydride (67.1 mg. 0.301 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. An additional amount of sodium triacetoxyborohydride (67.1 mg. 0.301 mmol) was then added and the reaction mixture was stirred at ambient temperature. After 1 h, no starting material remained. Saturated NaΗCO ₃ solution (30 ml) was added. then 20% MeOCH / ESM (30 ml) and the aqueous phase was extracted and then separated from the organic layer. The aqueous phase was again extracted twice with 20% MeOCH / ESM (2x30 ml). The combined organic extracts were dried over No. 18O ₄ . filtered and evaporated. getting a raw product. The crude product was purified by silica gel chromatography (0-20% MeOI / ESM). receiving 35 mg of the free base of the target compound in the form of a yellow solid (74.7%).

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Ή NMR (СОС1 ₃ , 400 MHz) δ 1.21-1.41 (m, 2Н), 1.76-1.92 (m, 2Н), 2.10-2.39 (m, 2Н), 2 , 41-2.52 (m, 1H), 2.61-2.79 (m, 2H), 2.86-2.98 (m, 1H), 3.05-3.14 (m, 1H) 3.72 (s, 2H), 4.18-4.29 (m, 4H), 4.38-4.43 (m, 1H), 4.51-4.62 (m, 1H), 4 94-5.05 (m, 1H), 6.33 (d, 1H), 6.58 (d, 1H), 6.80 (d, 1H), 7.77 (d, 1H), 7, 86 (s, 1H).

M8 (E8 +) t / ζ 468 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of ESM / MeOH and treated with 1 equiv. a solution of 1 M HC1 in EO. The solvents were removed and the solid was dried in a desiccator (P2O5) to give the desired compound as the hydrochloride in the form of a dark yellow solid (36 mg).

Example 58. (1H) -1 - [(4 - {[(8-Fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1piperidinyl) methyl] -1,2- dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride

Suspension (1 B) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-

3,8-dione dihydrochloride (for preparation see Example 13 (k) or 15 (ά)) (50 mg, 0.100 mmol) in chloroform (25 ml) and methanol (1.250 ml) at ambient temperature under nitrogen atmosphere was treated triethylamine (0.042 ml, 0.301 mmol) and stirred for 0.25 h (the suspension turned into a solution). Then, 8-fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde was added (for synthesis see ^ No. O 2007122258, Example 8 (b)) (19.62 mg, 0.100 mmol) and the reaction mixture stirred at ambient temperature for 0.5 hours. Sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was then added and the reaction mixture was stirred at ambient temperature. After 1 h, the starting material still remained, so sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The starting material still remained, so sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. Saturated NaHCO ₃ solution (30 ml) was added, then 20% MeOH / OCM (30 ml) and the aqueous phase was extracted and then separated from the organic layer. The aqueous phase was again extracted twice with 20% MeOH / OCM (2x30 ml). The combined organic extracts were dried Ya8O _4, filtered and evaporated to give crude product. The crude product was purified by silica gel chromatography (0-20% MeOH / OCM) to obtain 26 mg of the free base of the target compound in the form of a yellow solid.

Ή NMR (СОС1 ₃ , 400 MHz) δ 1.20-1.41 (m, 2Н), 1.72-1.89 (m, 2Н), 2.09-2.35 (m, 2Н), 2 , 42-2.52 (m, 1H), 2.55-2.78 (m, 2H), 2.85-2.99 (m, 1H), 3.08-3.15 (m, 1H) 3.63 (s, 2H), 4.22-4.48 (m, 5H), 4.51-4.63 (m, 1H), 4.95-5.06 (m, 1H), 6 32 (d, 1H), 6.61-6.72 (m, 2H), 7.75 (d, 1H), 7.89 (s, 1H).

M8 (E8 +) t / ζ 468 (MH ⁺ ).

The free base of the target compound was dissolved in a small amount of ESM / MeOH and treated with 1 equiv. a solution of 1 M HC1 in EO. The solvents were removed and the solid was dried in an desiccator (P ₂ O ₅ ) overnight to afford the title compound as a hydrochloride in the form of a yellow solid (26.6 mg, product correspondence).

Example 59. (1B) -1 - [(4- {[(2-Oxo-2H-chromen-7-yl) methyl] amino} -1-piperidinyl) methyl] -1,2-dihydro4H, 9H-imidazo [ 1,2,3-y] - 1,8-naphthyridine-4,9-dione

hdds

(1H) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine was added to a 10 ml round bottom flask -4,9-dione dihydrochloride (for the preparation, see example 5 A (])) (80 mg, 0.266 mmol), 2-oxo-2H-chromene-7-carbaldehyde (for the synthesis, see VO 2008009700, example 224 ) (46.4 mg, 0.266 mmol) and NaHCO ₃ (100 mg, 1.190 mmol) in dichloromethane (OCM) (4 ml) and methanol (1 ml) to give a brown solution. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. After 15 hours, sodium triacetoxyborohydride (113 mg, 0.533 mmol) was added and the reaction mixture was stirred at 25 ° C. under nitrogen for 4 hours. The reaction mixture was adsorbed onto silica gel and purified using 0-10% MeOH / OCM (1% X ₄ OH), obtaining the target compound as the free base (30 mg, 0.064 mmol, 24.07% yield) in the form of a tan solid. LBM8 and ¹ H NMR were consistent with the desired product.

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Ή NMR (Ό-4 MeOH, 400 MHz) δ 1.20-1.39 (m, 2H), 1.72-1.89 (m, 2H), 1.90-2.09 (m, 1H) 2.13-2.31 (m, 2H), 2.39-2.50 (m, 1H), 2.56-2.70 (m, 2H), 2.90-3.10 (m, 2H), 3.83 (s, 2H), 4.32-4.58 (m, 2H), 4.98-5.18 (m, 1H), 6.20-6.39 (m, 3H) 7.19-7.28 (m, 2H); 7.39-7.51 (m, 3H); 7.62-7.71 (m, 1H).

M8 (E8 +) t / ζ 459 (MH ⁺ ).

Example 60. (1K) -1 - [(4 - {[(7-Chloro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) methyl] amino } -1 piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione

(1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine was added to a 10 ml round bottom flask -4,9-dione dihydrochloride (for the preparation see example 5 (])) (45 mg, 0.134 mmol), 7-chloro-3,4-dihydro-2H-pyrido [3,2-b] [1, 4] oxazine-6-carbaldehyde (obtained (1) by reduction of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (in relation to synthesis cm. void 2003064421, example 15 (c)) using 1A1N ₄ to give (7-chloro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl ) methanol and then (2) oxidation using MnO ₂ ), (29.2 mg, 0.147 mmol) and No. ₁ HCO ₃ (100 mg, 1.190 mmol) in dichloromethane (ISM) (4 ml) and methanol (1 ml) to obtain a brown suspension. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. After 15 hours, sodium triacetoxyborohydride (56.6 mg, 0.267 mmol) was added and the reaction mixture was stirred at 25 ° C. under nitrogen for 4 hours. The reaction mixture was adsorbed onto silica gel and purified using 0-10% MeOH / OCM (1% ΝΗ ^ Η), obtaining the target compound as the free base (9.4 mg, 0.019 mmol, yield 14.57%).

Ή NMR (Ό-4 MeOH, 400 MHz) δ 1.49-1.70 (m, 2H), 2.00-2.17 (m, 2H), 2.28-2.49 (m, 2H) 2.72-2.81 (m, 1H), 2.89-2.94 (m, 1H), 3.05-3.20 (m, 3H), 3.38 (s, 2H), 3 50-3.58 (m, 1H), 4.18 (s, 2H), 4.20-4.24 (m, 2H), 4.434.50 (m, 2H), 5.08-5.18 (m, 1H), 6.28-6.35 (m, 2H), 7.06 (s, 1H), 7.78-7.83 (m, 2H).

M8 (E8 +) t / ζ 483/485 (MH ⁺ ).

Example 61. (1K) -1 - [(4- {[(7-Chloro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) methyl] amino } -1 piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione

(1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine was added to a 10 ml round bottom flask -4,9-dione dihydrochloride (for the preparation, see example 5A (])) (75 mg, 0.223 mmol), 7-chloro-3,4-dihydro-2H-pyrido [3,2-b] [1, 4] thiazine-6-carbaldehyde (obtained (1) by reduction of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde (in relation to for synthesis see VO 2003087098, example 306 (e)) using (7-chloro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) methanol and then ( 2) oxidation using MnO ₂ )) (47.8 mg, 0.223 mmol) and NaΗCO ₃ (100 mg, 1.190 mmo l) in ISM (4 ml) and methanol (1 ml), obtaining a brown suspension. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. After 15 hours, sodium triacetoxyborohydride (94 mg, 0.445 mmol) was added and the reaction mixture was stirred at 25 ° C. under nitrogen for 4 hours. The reaction mixture was adsorbed onto silica gel and purified using 0-10% MeOI / ESM (1% ΝΗ ^ Η), obtaining the target compound as the free base (45 mg, 0.090 mmol, yield 40.5%).

LBM8 and ¹ H NMR were consistent with the desired product.

Ή NMR (Ό-4 MeOH, 400 MHz) δ 1.20-1.45 (m, 2H), 1.65-1.92 (m, 2H), 2.19-2.39 (m, 2H) 2.42-2.71 (m, 2H), 2.82-3.10 (m, 5H), 3.65-3.80 (m, 4H), 4.40-4.50 (m, 2H), 5.05-5.20 (m, 1H), 6.25-6.35 (m, 2H), 7.22 (s, 1H), 7.72-7.83 (m, 2H) .

M8 (E8 +) t / ζ 483/485 (MH ⁺ ).

Example 62. (1K) -1 - ({4 - [(3,4-Dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) amino] -1piperidinyl} methyl) - 1,2-dihydro-4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9-dione

Suspension of (1K) -1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8naphthyridine-4,9-dione dihydrochloride (for preparation see Example 5A (])) (0.075 g, 0.02 mmol)

- 69 015821 in dichloromethane (5 ml) and methanol (1 ml) at ambient temperature in an argon atmosphere was treated with 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde ( obtained (1) reduction of 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carboxaldehyde (for the synthesis, see AO 2003087098, example 301 (ά)) using L1A1H ₄ to give 3,4-dihydro-2H-pyrido [3,2L] [1,4] thiazin-6-ylmethanol and then (2) oxidation using ΜηΟ ₂ )) (0.036 g, 0.02 mmol) , sodium bicarbonate (0.150 g, 1.786 mmol) and sodium sulfate (0.300 g, 2.112 mmol) and stirred at an ambient temperature narrowing medium for 5 hours. The solution was then treated with sodium triacetoxyborohydride (0.128 g, 0.603 mmol) and stirred for 65 hours. The solution was evaporated, suspended in CH ₃ OH, adsorbed onto silica gel and chromatographed on silica gel (0-15% CH ₃ OH in ΩΟ'Μ (with 1% ΝΉ / OH)), obtaining the target compound as the free base (59 mg, 63%) in the form of a beige solid.

Ή NMR (DMSOL ₆ , 400 MHz) δ 1.02-1.27 (m, 2H), 1.61-1.78 (m, 2H), 1.81-1.96 (s, 1H), 2 01-2.19 (m, 2H), 2.28-2.38 (m, 1H), 2.67-2.79 (m, 1H), 2.82-2.98 (m, 4H) 3.50 (s, 2H), 3.55-3.61 (m, 2H), 4.21-4.34 (m, 2H), 4.91-4.99 (m, 1H), 6 10-6.19 (m, 2H), 6.48-6.52 (d, 1H), 6.69-6.75 (s, 1H), 7.12-7.19 (d, 1H) 7.71-7.82 (d, 2H).

Μ8 (E8 +) t / ζ 465 (MH ⁺ ).

Example 63. 1 - [(4 - {[(2,3-Dihydro [1,4] oxathiino [2,3-c] pyridin-7-yl) methyl] amino} -1-piperidinyl) methyl] -1, 2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione hydrochloride (2: 1 mixture K: 8)

The target compound was obtained from 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9 Nimidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione ( 2: 1 mixture K: 8, for production see Example 11 (ά)) and

2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-carbaldehyde (for synthesis see AO 2004058144, example 60) according to the general method of example 12. NMR, LC-Μδ and monohydrochloride formation as in example 6A.

Example 64. 1 - ({4 - [([1,3] Oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H, 9H-imidazo [ 1,2,3-y] -1,8-naphthyridine-4,9-dione (2: 1 mixture 8: K)

The target compound was obtained from 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H, 9 Nimidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione ( 2: 1 mixture of 8: K, obtained analogously to example 11 (a-ά)), but using 7- (methyloxy) -1 - [(2K) -2-oxiranylmethyl] -3,4-dihydro-1,8- naphthyridin-2 (1H) -one (for the synthesis see Example 5 (D)) and 2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-carbaldehyde (for the synthesis, see AO 2004058144, example 60) according to the general method of example 12. Ή NMR, bC-Μδ and the formation of monohydrochloride, as in example 6A.

Compounds were prepared using the indicated starting materials according to the method of Example 5 (k), see table.

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Example number Salt form Structure Starting materials (with respect to the production of the above examples) 65 di-HC1 M8 (E5 +) ιη / ζ432 (ΜΗ ⁺ ) n __ <· ^Ν Χ__Ν heg ^Γν ° (1J) -1 - [(4-Amino 1-pyperidinyl) methyl] -k2 ’dihydro-4H, 9Ncmmmuo [1,2, ZC)] I, 8naphthyridine -4.9" dione dihydro chloride (Example 5A (])) 1 H-imidazo [4,5-b] pyridine- 2-carb aldehyde (commercial) (1K) -1 - [(4-amino-1-lylermdinyl) methyl] -1,2 dihydro-4 N, 9 Nimidazo [1D, 8- naftnryadin-4,9-dnon dihydrochloride (Example 5 A ())) 1 H-pyrrolo [2,3-L1-pyridine-2-carbaldehyde (commercial) 66 free base M & (E5 c τη / ζ43ϊ (ΜΗ ⁺ ) ΊΧΓ 67 DI-NS1 M8 (E8 +) t / ζ 480 (MH +) Hhg (1 K) -1 - [(4-amino-1liperidinyl) methyl] -1,2 dihydro O'4H, 9H 'imidazo [1,2 ”3-y] -1 Lnaftnridine-4,9-dione dihydrochloride (Example 5A < 3 " 8'Fluoro-3-OXO-3.4-d and hydroxy 2H-1,4 * benzoxazine-bcarbaldehyde (in regarding synthesis see No. 02006014580 Production Example 15) 68 di-HC1 M3 (E8 +) t / ζ 466 (MH +) xTX (1 K) -1 - ((4-amino-1 piperidinyl) methyl) -1,2 dihydro-4H, 9 Nimidazo [1,2,3'U1-1,8 naphthyridine "4,9'dione dihydrochloride

- 71 015821

(Example 5 Α (ϊ)) 8-fluoro-3,4-dihydro-2H'1,4 · benzoxazine-6carbaldehyde Obtained (I) by reduction of 8-fluoro-Zoxo-3,4-dihydro-2H · 1,4benzoxazine '6'carbidedehyde (for synthesis see No. 02006014580 Production Example 15) Using IA1H <(8fluoro'ZD'Hydro-ZN-1,4-benzoxazin-6yl) methanol and then (2) oxidation using MnO _:) ) 69 free base M8 (E5 +) t / g484СМН ⁺ ) hhg (1K) -1 - [(4-amino-L pnperidinyl) methnl] -1.2 dm hydro-4H, 9H * imidazo [1,2,3- |]] - 1,8naphthyridine * 4,9- Dnon dihydrochloride (Example 5Af) 7.8-Difluoro-3,4-dihydro-2H-1,4 "benzoxazsts-6carbaldehyde Obtained (1) by reduction of 7,8 difluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-methylcarboxylate with using ΕιΑΙΗι to give (7,8-difluoro3,4-dihydro-2H-1,4benzoxazine-bil) methanol and then (2) oxidation using MnCb))

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70 free base M8 (E8 +) τη / ζ 513/515 (MH +) hhg (1K) -b [(4-amino-b piperidinyl) methyl] -1.2 dngadro-4H, 9 Nimidazo [1 DZ-c] -1.8 naphthyridine-4,9-dione dihydrochloride (Example 5 Af) 7-Chloro- 3-oxo-3,4-dihydro2H-pyrido [3,2 BCl1,4) thiazmn-bcarbaldehyde (for synthesis see No. 003087098 ExZO6 (e)) 71 Mopo-HC1 M8 (E8 +) t / ζ 453 (MH ⁺ ) l-hSnaA) XXX (1st.) - 14 (4-amino-1gasheridnyl) methyl] -1,2 dihydro-4C, 9 Nimidazo [1,2,3-ΐί] -1,8 · nafl1ridin-4.9-D} yun dihydrochloride (Example 5Af " 6,7-Di hydro-5 N-thieno [3,2b] pyran-2-carbaldehyde (for synthesis see No. 02007122258 Example 88 (c)) 72 Mopo-HC1 M8 (E8 +) t / ζ 454 (MH ⁺ ) (2k) -2 - {(4-amino-1-piperdinyl) methyl} -1,2-dihydro-ЗК8Н-2а, 5,8-triezaacenaphthylene-3,8dion (Example 16A0) method B) 6,7-Dihydro-5H-thieno (3,2 b] pyran-2-carbaldehyde Example 88 (c)) 73 Mopo-NS! M8 (E8 +) t / ζ 454 (MH +) _g αΟήСр) χχτ ⁰ (1B> 1 - ((4-amino-b-pyleridinyl) methyl] -1,2 dihydro-3H, 8H-2a, 5.8 atriazac naphthylene-3,8dione dihydrochdoride (Example B (E) or 15 (D)) 6, 7-dihydro-5H-thieno (3.2b] pyran-2-carbaldehyde (for synthesis see No. 02007122258

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Example 88 (c)) 74 DI-NS1 M8 (E8 +) t / ζ 448 (ΜΗΌ ¹ - TP ⁰ (1K) -CH (4-Amtsno-1- piperidinyl) methyl] '1,2-dihydro * 4H, 9 Nimidazo (1,2,3 - ^) - 1,8 naphthyridine-4,9-dione DIGYDROCHLORIDE (commercial) 75 DI-NS1 M8 (ЕЗ +) t / ζ 492 (МН ⁺ ) ° hig (1K) -1 - [(4-Amnno-1 piperidinyl) methyl) -1,2 dihydro-4H, 9 Nimmdazo [1,2,5 - //) - 1,8 naphthyridine CH ^ dione dihydrochloride (Example 5A (]}) 4 -oxo -2.3, 4> 5-tetrages dro1,5-bsnzotmazepine-7carbaldehyde (for synthesis see ^ 02004058144 Example 128 (e) 76 di ns! M5 (E8 +) t / ζ 463 (MH ⁺ ) / - (5 - / N K / S Oi (1 & H - [(4-Amino-1 and impervinyl) methst] -1,2 dnghydroCHN, 9 Nimidazo [1,2,3-ϋ] '1,8 naphthyridine-4,9-dione dihydrochloride (Example 5Af) 8-Methyl-2, E “DIHydro-1,4benzodioxin-6carbaldehyde (obtained from 8-bromo-2,3-dihydro-1,4benzodioxin-6carbaldehyde (for synthesis see 72007122258 Example 31 (c)) by palladium-catalyzed reaction of a 5ty1e combination using tetramethyltin)

- 74 015821

77 free base M3 (E8 +) ιη / ζ464 (ΜΗ ⁺ ) ΧΙΤ (1 K.) - 1 - ((4-amino-1- piperidinyl) x * ethyl] -1,2 dihydro-4H, 9 Nimidazo [1 ^, 3-1)) - 1,8 naphthyridium-4,9-dione dihydrochloride (Example 5Af) 3,4'Dihydro-2H-1,4benzothiazine-6carb aldehyde (for synthesis see No. 02003087098 Example 214) 78 DI-NS1 M3 (ЕЗ +) t / ζ 478 (МН ⁺ ) ha ° (1 &) - 1 - [(4-Amino Chiperidiyl) methyl} -1,2 dihydro-4H, 9 Nimidazo [1,2,3’C] -1,8 naphthyridine-4,9-dione dihydrochloroinp (Example 5Af) 2.3.4.5- Tetrahydro-1,5benzothiazepn-7carbalpegide {obtained from 4-0X00-2,3,4,5tetrahydro-1,5benzothiazepin-7methylcarboxylate (for synthesis see No. 02007016610, Preparation Example 18 (c)) by treatment with a borane complex TNG to obtain 2.3.4.5-tetrahydro-1,5benzotvazepine-7methylcarboxylate, then treatment of the obtained compound ΕίΑΙΗφ to obtain 2,3,4,5tetrahydro · 1,5benzothiazepine-7nlmethanol and the final treatment of MnOa

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79 DI-NS1 M8 (E5 +) t / ζ 4bb (MH ⁺ ) hg ^r (1K) -1 - [(4-amino-1-piperdini ^ megi l] -1,2 dihydro-4H, 9H- naphthyrndine-4.9-dione dihydrochloride (Example 5 Af) 7-fluoro-3,4'DIGUIDRO-2H-1,4benzoxazine-6-carbaldehyde (obtained from 7-fluoro-Zoxo-3,4-dihydro-2H-1,4benzoxazine -6 carbonitrile (for synthesis see XV02002056882, Example 8 (b)) by treatment with diisobutylaluminum hydride)

Production Example A. 6,7-Dihydro [1,4] dioxino [2,3-c] pyridazine-3-carbaldehyde.

(a) 3,4,6-Trichloropyridazine.

It was obtained by a slight modification of the method described by Kazpag e1 a1., Nis1eo8 ^ 8e8 & Nis1eoΐ ^ 8e8 (1994), 13 (1-3), 459-79.

Hydrazine sulfate (51 g) was suspended in water (250 ml), heated under reflux and bromomaleic anhydride (90.38 g) was added dropwise. The mixture was heated under reflux for 4 hours, then cooled to ambient temperature. The reaction was repeated with 29 g of hydrazine sulfate, 53 g of bromo maleic anhydride and 130 ml of water. The precipitate was collected by filtration, washed with water and acetone, and dried as a combined charge in vacuo to give 4-bromo-1,2-dihydro-3,6-pyridazinedione as a white solid (113 g).

This solid in two batches was treated with phosphorus oxychloride (2x200 ml) and heated under reflux for 3.5 hours. The mixture was cooled, evaporated and azeotropically treated with toluene. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and an additional two times were extracted with an ESM. The organic extracts were dried and evaporated. This residue was redissolved in dichloromethane and chromatographed on silica gel (300 g) (ESM as eluent) to give a white solid (101.5 g, 87%). (Analysis of L / M8 showed approximately 20-30% of impurities, isomers of bromo-dichloropyridazine).

M8 (+ уе ion electrospray) t / ζ 184/185/186 (МН ⁺ ), trichloropyridazine.

M8 (+ уе ion electrospray) t / ζ 228/229/231 (МН ⁺ ), bromo-dichloropyridazine.

(b) 2 - [(3,6-Dichloro-4-pyridazinyl) hydroxy] ethanol.

A solution of ethylene glycol (55 ml) in tetrahydrofuran (200 ml) was treated at approximately 0 ° C (ice bath) with sodium hydride (60% dispersion in oil, 5.9 g) for 40 minutes. After complete addition, 3,4,6-trichloropyridazine (27 g) containing bromo-dichloropyridazine isomers as impurities was added in portions and washed with dry THE (50 ml), the mixture was stirred at 0 ° C for 1 h and then at ambient temperature Wednesday over night. The mixture was concentrated (to 1/3 of the volume), then was diluted with an aqueous solution of sodium bicarbonate and was extracted with chloroform (5g) and ethyl acetate (3G). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated, and the solids were filtered and washed with CHC1 ₃ (3g) and dried in a vacuum oven overnight at 40 ° C to obtain a white solid (25.5 g, 83% ) containing a certain amount of bromine substituted derivative (10-15%).

М8 (+ уе ion electrospray) t / ζ 209/211 (МН ⁺ ).

M8 (+ уе ion electrospray) t / ζ 255/7 (МН ⁺ ), bromine-substituted derivative.

(c) 3-Chloro-6,7-dihydro [1,4] dioxino [2,3-c] pyridazine.

A solution of 2 - [(3,6-dichloro-4-pyridazinyl) oxy] ethanol containing a certain amount of the bromo-substituted derivative (15.46 g; 0.0703 mol) in dry 1,4-dioxane (1.2 L) was treated with hydride lithium (2.3 g; 0.28 mol), added in portions and stirred at ambient temperature for 1 h in argon atmosphere, then heated at 110 ° C overnight. The reaction was quenched with wet 1,4-dioxane, then cooled with a mixture of ice water. The solution was evaporated to half volume, pH 8 was adjusted with 5 M hydrochloric acid and evaporated to dryness. Water was added and the residue was extracted with 5x chloroform, dried (sodium sulfate) and evaporated to give a white solid (12.4 g, approximately 77%) (containing approximately 15% brominated compound).

M8 (+ уе ion electrospray) t / ζ 173/5 (С1 МН ⁺ ); 217/9 (Br MH ⁺ ).

76 015821 (ά) 3-Ethenyl-6,7-dihydro [1,4] dioxino [2,3-c] pyridazine.

A solution of 3-chloro-6,7-dihydro [1,4] dioxino [2,3-c] pyridazine (13.6 g, 0.079 mol) containing approximately 15% bromo-substituted compound in dimethoxyethane (400 ml) was degassed in the atmosphere argon for 10 min, then tetrakis- (triphenylphosphine) palladium (0) (2 g), potassium carbonate (10.33 g), a complex of 2,4,6-trivinylcyclotriboroxane and pyridine (11.32 g) and water ( 55 ml). The mixture was heated at 95 ° C. for 48 hours and cooled and evaporated to dryness. The mixture was treated with an aqueous sodium bicarbonate solution and extracted (5g) with an ESM. The extracts were dried (sodium sulfate), evaporated and the residue was chromatographed on silica gel (500 g), eluting with 0-100% ethyl acetate-hexane to give the product (6.43 g, 50%) [also some crude fractions (1.8 g) ].

M8 (+ ye ion electrospray) t / ζ 165 (MH ⁺ ).

(e) Target compound.

A solution of 3-ethenyl-6,7-dihydro [1,4] dioxino [2,3-c] pyridazine (11.58 g) in a mixture of 1,4-dioxane / water (600 ml / 180 ml), cooled on ice were treated with an aqueous solution of osmium tetroxide (4% w / v, 25 ml) and sodium periodate (43 g). This mixture was allowed to warm to ambient temperature and after 7 hours while stirring, the mixture was evaporated to dryness and azeotropically treated with 1,4-dioxane. Silica gel, 1,4-dioxane and chloroform were added and the mixture was evaporated to dryness overnight, then added to a silica gel column (400 g) and chromatographed, eluting with chloroform, then 0-100% ethyl acetate in hexane to give a white solid (7 55 g, 64%).

M8 (+ ye ion electrospray) t / ζ 167 (MH ⁺ ).

Biological activity.

Antimicrobial activity test.

Full-cell antimicrobial activity was determined by microdilution of the broth using the procedure recommended by the Institute of Clinical and Laboratory Standards (C81), Document M7-A7, Methods for Dilution Testing for Bacteria that Grow Aerobically. Compounds were tested in serial two-fold dilutions in the range of 0.016 to 16 μg / ml.

The minimum inhibitory concentration (M1C) was defined as the lowest concentration of the compound that inhibited visible growth. A mirror reader was used to help determine the result of M1C.

Compounds were evaluated against gram-positive organisms selected from 81 aryosossossi igeeik, 81gerosossiys rieitoshe, 81ergosossiys rodeyeks, E1eossossik Gaes11 <and E1egosossik Gaesst.

In addition, the compounds were evaluated against gram-negative organisms selected from Naetorhulpidae, Peptenoricensae, and Leuchebaceae.

Each of the listed examples identified in the present invention, except for examples 71-73 and 76-79, was checked in the form of at least one illustrated salt or in the form of a free base. Unless otherwise indicated, the tested examples had M1C <2 μg / ml against a strain of at least one of the above organisms, with the exception of Example 9, which had M1C <4 μg / ml against a strain of at least one of the above organisms. For at least one strain of each of the above organisms, at least one example had M1C <2 μg / ml.

Inhibition test MusoBac1gst 1bbbc1o818 H37Ku.

Measurement of the minimum inhibitory concentration (M1C) for each tested compound was carried out in 96-well flat-bottomed polystyrene microtiter plates. Carried out 10 double dilutions of the drug in pure dimethyl sulfoxide, starting with 400 μm. 5 μl of these drug solutions were added to 95 μl of M ^ άά1eB ^ oo 7H9 medium. (Lines A-N, rows 1-10 on the tablet). Isoniazid was used as a positive control, 8 twofold dilutions of isoniazid were prepared, starting from 160 μg / ml ^-1 , and 5 μl of this control curve was added to 95 μl M ^ άά1eB ^ oo 7H9 (E | Gso Ca! A1odium KeG. 271310) NPP environment (Vesloy Oyktkop Ca1a1ode KeG. 211887). (Row 11, lines AH). 5 μl of pure DMSO was added to row 12 (growth and pure control).

The inoculum was standardized to approximately 1x10 ’CFU / ml and diluted 1 in 100 in M ^ S1EbOoc 7H9 + AES and 0.025% T \ uep 80 (81dta P4780) medium to obtain the final inoculum of the H37Ku strain (ATCC25618). 100 μl of this inoculum was added to all plates except C-12 and H-12 wells (pure control). All tablets were placed in a sealed box to prevent drying of the peripheral wells and incubated at 37 ° C without agitation for 6 days. A solution of diazorezorcin was prepared by dissolving one tablet of diazorezorcin (tablets of thiazorezorcin for testing milk; KeG 330884 ννκ 1i1egiaEoia1 B-Ιά) in 30 ml of sterile PB8 (phosphate buffered saline). 25 μl of this solution was added to each well. Fluorescence was measured (8 samples of M5 Mo1eci1ag Oeucek, excitation 530 nm, emission 590 nm) after 48 h to determine the value of M1C.

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Examples 1-4, 5A, 6A, 7-9, 12, 13A, 14, 15, 16A, 17A, 19A, 20, 23-32, 34, 37-44, 46-50, 53-57, 59 and 63 tested in the test for inhibition of Muso bac1epit 1begi1o818 H37Kt.

Examples 2, 4, 5A, 6A, 7, 8, 12, 13A, 14, 16A, 19A, 20, 23-26, 28-32, 34, 37, 39, 40, 42, 44, 46, 49, 50 56, 59 and 63 showed an M1C value below 2.0 μg / ml.

Examples 4, 5A, 7, 8, 12, 13A, 14, 16A, 19A, 25, 26, 30-32, 37, 40, 49, 50, and 56 showed an M1C value of 1.0 μg / ml or lower.

Claims (20)

CLAIM 1. The compound of formula (I) or its pharmaceutically acceptable salt and / or Ν-oxide a — ΝΚ ² —in ⁵ in which Ζ ¹ and Ζ ^{2 are} independently selected from CH and Ν; K ^1a and K ^{1b are} independently selected from hydrogen; halogen; cyano; (C1 _-6 ) alkyl; (C1 _-6 ) alkylthio; trifluoromethyl; trifluoromethoxy; carboxy; hydroxy, optionally substituted _(C1-6) alkyl or (C1 _-6) alkyloxy (C1 _-6) alkyl; (C _{! -6} ) alkoxy substituted (C1 _-6 ) alkyl; hydroxy (C _{! -6} ) alkyl; amino groups, optionally Ν-substituted by one or two (C1 _-6 ) alkyl, formyl, (C1 _-6 ) alkylcarbonyl or (C1 _-6 ) alkylsulfonyl groups; and aminocarbonyl, in which the amino group is optionally substituted with (C1 _-4 ) alkyl; provided that K ^1a is H when обозначает ² is Ν and K ^1b is H when Ζ ¹ is Ν; K ² denotes hydrogen or (C1 _-4) alkyl or together with R ⁶ forms Υ, as defined below; A denotes a group (ί) (1b) in which K ³ has the meanings defined for K ^1a and K ^1b , or denotes oxo; n is 1 or 2; or A denotes the group (ίί) (ίί) waiting for ν ³ and Ν; X is O, SK ⁴ K ⁸ or ΝΚ ⁶ ; one K ⁴ has the meanings defined for K ^1a and K ^1b , and the rest and K ⁸ denote hydrogen or one K ⁴ and K ⁸ together denote oxo, and the rest denote hydrogen; K ⁶ is hydrogen or (C1 _-6) alkyl or together with R ² forms Υ; K ⁷ is hydrogen; halogen; hydroxy, optionally substituted with ( _C1-6 ) alkyl; or (C1 _-6 ) alkyl; Υ is SK ⁴ K ⁸ CH ₂ ; CH ₂ SC ⁴ K ⁸ ; (C = O); SK ⁴ K ⁸ ; SK ⁴ K ⁸ (C = O) or (C = O) SK ⁴ K ⁸ or when X is SK ⁴ K ⁸ , K ⁸ and K ⁷ together represent a bond; and selected from CO and CH ₂ and K ⁵ denotes, if necessary, a substituted bicyclic carbocyclic or heterocyclic ring system (B) (B) containing up to four heteroatoms in each ring in which at least one of rings (a) and (b) is aromatic; X ¹ is C or Ν when it is part of an aromatic ring, or CK ¹⁴ when it is part of a non-aromatic ring; X ² denotes Ν, ΝΚ ¹³ , O, 8 (O) _X , CO, or SK ¹⁴ when it is part of an aromatic or non-aromatic ring, or may also indicate SK ¹⁴ K ¹⁵ when it is part of a non-aromatic - 78 015821 rings; X ³ and X ⁵ independently represent Ν or C; Υ ¹ denotes a linker group of 0-4 atoms. each atom of which is independently selected from Ν. ΝΚ ¹³ . O. 8 (O) _X. CO and SY ¹⁴ . when it is part of an aromatic or non-aromatic ring. or may additionally be CJ ¹⁴ I ¹⁵ . when it is part of a non-aromatic ring; Υ ² denotes a linker group of 2-6 atoms. and each atom Υ ^{2 is} independently selected from Ν. ΝΚ ¹³ . O. 8 (O) ^X. CO. SE ¹⁴ . when it is part of an aromatic or non-aromatic ring. or may additionally be CJ ¹⁴ I ¹⁵ . when it is part of a non-aromatic ring; each of I ¹⁴ and I ^{15 is} independently selected from H; (C1 _-4 ) alkylthio; halogen; carboxy (C1 _-4 ) alkyl; (C1 _-4 ) alkyl; (C1 _-4 ) alkoxycarbonyl; (C1 _-4 ) alkylcarbonyl; (C1 _-4 ) alkoxy (C1 _-4 ) alkyl; hydroxy; hydroxy (C1 _-4 ) alkyl; (C1 _-4 ) alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl. if necessary, mono - or disubstituted (C1-4) alkyl; or I ¹⁴ and I ¹⁵ can together mean oxo; each I ¹³ independently represents H; trifluoromethyl; (C1 _-4 ) alkyl. optionally substituted hydroxy. (C1-6) alkoxy. (C1-6) alkylthio. halogen or trifluoromethyl; (C2-4) alkenyl; (C1-4) alkoxycarbonyl; (C1-4) alkylcarbonyl; (C1-6) alkylsulfonyl; aminocarbonyl. in which the amino group, if necessary, mono - or disubstituted (C1-4) by alkyl; and each x independently means 0. 1 or 2. 2. The compound according to claim 1. wherein: (ί) Ζ ¹ and Ζ ² . both. denote CH; (ίί) Ζ ¹ is N and Ζ ² is CH; (ΐϊϊ) Ζ ¹ stands for CH and Ζ ² stands for Ν. 3. The compound according to any one of claims 1 or 2. in which ^Ia is hydrogen and ^Ia is hydrogen. 4. The compound according to any one of claims 1 to 3. in which A denotes (1A). n = 1 and H ³ is H or hydroxy at position 3; A is (ίί); X represents CJ ⁴ I ⁸ ; where I ⁸ denotes H and I ⁴ denotes H or OH; or A is (ίί); X is O; I ⁷ is H and V ¹ . V ² and V ³ . everyone. denote CH ₂ . 5. The compound according to claim 4. wherein A is piperidin-4-yl or pyrrolidin-4-ylmethyl. 6. The compound according to any one of claims 1 to 5. in which υ is CH ₂ . 7. The compound according to any one of claims 1 to 6. in which I ⁵ denotes an aromatic heterocyclic ring (B). having 8-11 ring atoms. including 2-4 heteroatoms. of which at least one is Ν or ΝΚ ¹³ ; Υ ² contains 2-3 heteroatoms. one of which is 8 and 1-2 are Ν. moreover, one Ν is connected with X ³ . or a heterocyclic ring (B) has an aromatic ring (a). selected from. if necessary. substituted benzo. pyrido. pyridazino and pyrimidino. and ring (b) is non-aromatic; and Υ ² has 3-5 atoms. including at least one heteroatom. where O. 8. CH2 or ΝΕ ¹³ is associated with X ⁵ . and I ¹³ is different from hydrogen. and either ΝΗί'Ό is connected through Ν to X ³ . either O. 8. CH2 or ΝΗ are linked to X ³ . 8. The compound according to any one of claims 1 to 6. in which I ^{5 is} selected from the following compounds: 3-oxo-3.4-dihydro-2H-pyrido [3.2-b] [1.4] oxazin-6-yl; 3-oxo-3.4-dihydro-2H-pyrido [3.2-b] [1.4] thiazin-6-yl; 2.3-dihydro [1.4] dioxino [2.3-c] pyridin-7-yl; [1.3] oxathiolo [5.4-c] pyridin-6-yl; 6-fluoro-2.3-dihydro-1.4-benzodioxin-7-yl; 2.3-dihydro [1.4] oxathiino [2.3-c] pyridin-7-yl; 3.4-dihydro-2H-pyrano [2.3-s] pyridin-6-yl; 5-fluoro-2.3-dihydro-1.4-benzodioxin-7-yl; 5-carbonitro-2.3-dihydro-1.4-benzodioxin-7-yl; 2.3-dihydrobenzo [1.4] dioxin-6-yl. 9. The compound according to claim 1. selected from the following compounds: 1 - ({4 - [(2.3-dihydro [1.4] dioxino [2.3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1.2 dihydro-3H.8H-2a.5.8a-triazacenaphthylene- 3.8-dione; 1 - ({4 - [([1.3] oxathiolo [5.4-s] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1.2-dihydro-4H.9 Nimidazo [1.2.3-y] -1.8 - naphthyridine 4.9 dione; 1 - ({4 - [(2.3-dihydro [1.4] dioxino [2.3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1.2 dihydro-4H.9H-imidazo [1.2.3-y ] -1.8-naphthyridine-4.9-dione; 1 - ({4 - [(7-bromo-3-oxo-3.4-dihydro-2H-pyrido [3.2-b] [1.4] thiazin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1.2-dihydro -4H.9H-imidazo [1.2.3-y] -1.8-naphthyridine-4.9-dione; (1H) -1 - ({4 - [([1.3] oxathiolo [5.4-s] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1.2-dihydro4H.9H-imidazo [1.2.3-y ] -1.8-naphthyridine-4.9-dione; (1H) -1 - ({4 - [(2.3-dihydro [1.4] oxathiino [2.3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) - 1.2-dihydro-4H.9H-imidazo [1.2.3-y] -1.8-naphthyridine-4.9-dione; (1H) -1 - ({4 - [(5.6.7.8-tetrahydro-3-isoquinolinylmethyl) amino] -1-piperidinyl} methyl) -1.2-dihydro - 79 015821 4H, 9H-imidazo [1,2,3-y] - 1,8-naphthyridine-4,9-dione; (1B) -1 - ({4 - [(6,7-dihydro-5H-cyclopenta [c] pyridin-3-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H, 9H-imidazo [ 1,2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - ({4 - [(1,3-dihydrofuro [3,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro4H, 9H-imidazo [ 1,2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - ({4 - [(3,4-dihydro-2H-pyrano [2,3-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; 7 - [({1 - [(4,9-dioxo-1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridin-1-yl) methyl] -4 piperidinyl } amino) methyl] -2,3-dihydro-1,4-benzodioxin-5-carbonitrile; 1- [(4 - {[(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-4H, 9H imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - ({4 - [([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a 5,8a-triazacenaphthylene-3,8-dione; (1B) -1 - ({4 - [(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) - 1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione; (1B) -1 - ({4 - [(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro 3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (2B) -2 - ({4 - [([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a 5,8a-triazacenaphthylene-3,8-dione; (28) -2 - ({4 - [([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a 5,8a-triazacenaphthylene-3,8-dione; 2- ({4 - [([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro-3H, 8H2a, 5.8a triazacenaphthylene-3,8-dione; (2B) -2 - ({4 - [(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) - 1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione; 2 - ({4 - [(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-3H, 8H- 2a, 5,8a-triazacenaphthylene-3,8-dione; (28) -2 - ({4 - [(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) - 1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione; 2 - ({4 - [(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-3H, 8H- 2a, 5,8a-triazacenaphthylene-3,8-dione; (1B) -1 - ({4 - [(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -4-methyl-1 piperidinyl} methyl) -1, 2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - ({4-methyl-4 - [([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (2B) -2 - ({4 - [(2,1,3-benzothiadiazol-5-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro-3H, 8H2a, 5,8a-triazacenaphthylene- 3,8-dione; (2B) -2 - [(4- {[(7-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-3H 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (2B) -2 - ({4 - [(3,4-dihydro-2H- [1,4] oxathiepino [2,3-c] pyridin-8-ylmethyl) amino] -1piperidinyl} methyl) -1.2 dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (2B) -2 - ({4 - [([1,3] oxathiolo [4,5-s] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a 5,8a-triazacenaphthylene-3,8-dione; (2B) -2 - [(4 - {[(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) methyl] amino} -1 piperidinyl ) methyl] -1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (1B) -1 - ({4 - [(2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro4H, 9H-imidazo [1, 2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - [(4 - {[(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-4H 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - [(4 - {[(7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) methyl] amino} -1 piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - [(4 - {[(4-chloro-7-oxo-6,7-dihydro-1H-pyrimido [5,4-b] [1,4] oxazin-2-yl) methyl] amino} -1 piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - [(4 - {[(7-oxo-6,7-dihydro-1H-pyrimido [5,4-b] [1,4] thiazin-2-yl) methyl] amino} -1 piperidinyl ) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1B) -1 - ({4 - [(1,2,3-benzothiadiazol-5-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro-4H, 9 Nimidazo [1,2,3- y] -1.8-naphthyridine-4.9-dione; (1B) -1 - ({4 - [(2,3-dihydro-1-benzofuran-5-ylmethyl) amino] - 1-piperidinyl} methyl) -1,2-dihydro4H, 9H-imidazo [1,2, 3-y] - 1,8-naphthyridine-4,9-dione; (1B) -1 - ({4 - [(3,4-dihydro-2H-pyrano [2,3-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (1B) -1 - ({4 - [(2,3-dihydrofuro [2,3-c] pyridin-5-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro 80 015821 3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (2K) -2 - ({4 - [(2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a, 5, 8a-triazacenaphthylene-3,8-dione; (2K) -2 - [(4- {[(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-3H 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; 7 - {[(1 - {[(2K) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-2-yl] methyl} -4 piperidinyl) amino] methyl} -2,3-dihydro-1,4-benzodioxin-5-carbonitrile; (2K) -2 - ({4 - [(2,3-dihydrofuro [2,3-c] pyridin-5-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (1K) -1 - ({4 - [(2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro3H, 8H-2a, 5, 8a-triazacenaphthylene-3,8-dione; (1K) -1 - ({4 - [([1,2,5] thiadiazolo [3,4-b] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-4H, 9H imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1K) -1 - [(4 - {[(4-fluoro-1H-benzimidazol-2-yl) methyl] amino} -1-piperidinyl) methyl] -1,2-dihydro4H, 9H-imidazo [1,2 , 3-y] - 1,8-naphthyridine-4,9-dione; (1K) -1 - [((28) -2 - {[([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] methyl} -4-morpholinyl) methyl] - 1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1K) -1 - {[(28) -2 - ({[(7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6yl ) methyl] amino} methyl) -4-morpholinyl] methyl} -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9dione; (2K) -2 - ({4 - [([1,2,5] thiadiazolo [3,4-b] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2 dihydro-3H, 8H -2a, 5.8a-triazacenaphthylene-3,8-dione; (1K) -1 - ({4 - [(3,4-dihydro-2H-chromen-7-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro-4H, 9 Nimidazo [1,2, 3-y] -1.8-naphthyridine-4.9-dione; (1K) -1 - ({4 - [(2,3-dihydro-1-benzofuran-6-ylmethyl) amino] - 1-piperidinyl} methyl) -1,2-dihydro4H, 9H-imidazo [1,2, 3-y] -1,8-naphthyridine-4,9-dione; (1K) -1 - ({4 - [(3,4-dihydro-2H-chromen-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro-4H, 9 Nimidazo [1,2, 3-y] -1.8-naphthyridine-4.9-dione; (2K) -2 - [(4 - {[(5-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-3H 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (1K) -1 - {[(2K) -2 - ({[((7-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} methyl) -4morpholinyl] methyl} - 1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1K) -1 - [((38) -3 - {[([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] methyl} -1-pyrrolidinyl) methyl] - 1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; 7 - {[(1 - {[(1K) -3,8-dioxo-1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-1-yl] methyl} -4 piperidinyl) amino] methyl} -2,3-dihydro-1,4-benzodioxin-5-carbonitrile; (1K) -1 - [(4 - {[(7-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-3H 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (1K) -1 - [(4 - {[(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-3H 8H-2a, 5,8a-triazacenaphthylene-3,8-dione; (1K) -1 - [(4 - {[(2-oxo-2H-chromen-7-yl) methyl] amino} -1-piperidinyl) methyl] -1,2-dihydro-4H, 9 Nimidazo [1,2 , 3-y] -1.8-naphthyridine-4.9-dione; (1K) -1 - [(4 - {[(7-chloro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) methyl] amino} -1 -piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1K) -1 - [(4 - {[(7-chloro-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) methyl] amino} -1 -piperidinyl) methyl] -1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; (1K) -1 - ({4 - [(3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-ylmethyl) amino] -1-piperidinyl} methyl) - 1,2-dihydro-4H, 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; 1 - [(4 - {[(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-yl) methyl] amino} -1-piperidinyl) methyl] -1,2 dihydro-4H 9H-imidazo [1,2,3-y] -1,8-naphthyridine-4,9-dione; 1 - ({4 - [([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) -1,2-dihydro-4H, 9 Nimidazo [1,2 , 3-y] -1.8-naphthyridine-4.9-dione; or free base compounds from the table - 81 015821 or its pharmaceutically acceptable salt. - 82 015821 10. (2H) -2 - ({4 - [(3,4-Dihydro-2H-pyrano [2,3-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) - 1,2-dihydro-3H, 8H-2a, 5,8a-triazacenaphthylene-3,8-dione or a pharmaceutically acceptable salt thereof. 11. (2H) -2 - ({4 - [(3,4-Dihydro-2H-pyrano [2,3-c] pyridin-6-ylmethyl) amino] -1-piperidinyl} methyl) - 1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3,8-dione hydrochloride. 12. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for use in the treatment of bacterial infections in mammals. 13. The use of claim 12 in the treatment of infections of the upper and / or lower respiratory tract, skin and soft tissue infections, urinary tract infections and / or tuberculosis. 14. The use of a compound according to claim 10 or 11 for the manufacture of a medicament for use in the treatment of bacterial infections in mammals, in which the bacterial infection is caused by a gram-positive organism selected from 81 aryosossicus erythemae, 81erosossic erythrocytes, E1erossossus erythrocytes, and Euler an organism selected from Nahexperidae nigella / ae, Mogache11a caulpidae118, Excepus coi11, Rkuschotiak aegzdtoka, Proteus somidae, E1eobacterium eustheneusa, Kelo 81 a mountain of notepa8 taLoria or musoaclischus 1 and esci1o818. 15. The compound according to any one of claims 1 to 11 for use in therapy. 16. The compound according to any one of claims 1 to 11 for use in the treatment of bacterial infections in mammals. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition comprising a compound of claim 10 or 11 and a pharmaceutically acceptable carrier. 19. The compound of formula (SHA) of formula (ΙΙΙΒ) or formula (8) (8) • y. 'Y U' Y Y Ί in which L is -Λ-Ν (Ρ, where B is hydrogen, B is B or a group that can be converted into it; A, B ² , B ¹ 'and B ^{1 b} have the meanings defined in paragraph 1. 20. (2B) -2- | (4-amino-1-piperidinyl) methyl] -1,2-dihydro-3H, 8H-2a, 5.8a-triazacenaphthylene-3.8 dione.